Stem Cell Treatment Heart Disease

Stem Cells and Heart Disease

Stem Cell Treatments for Heart Disease is an Option

Cardiovascular diseases remain the biggest cause of deaths worldwide, though over the last two decades, cardiovascular mortality rates have declined in many high-income countries but have increased at an astonishingly fast rate in low- and middle-income countries. The percentage of premature deaths from cardiovascular disease range from 4% in high-income countries to 42% in low-income countries. More than 17 million people died from cardiovascular diseases in 2008. Each year, heart disease kills more Americans than cancer. In recent years, cardiovascular risk in women has been increasing and has killed more women than breast cancer.

Measures to prevent cardiovascular disease may include:

  • Keeping unapposed simple carbohydrates under control, no matter what type: fruit, bread, dairy, etc.
  • decrease emotional stress, or how you react to the environment (traffic, work, deadlines, lifestyle, etc.)
  • a low fat high fiber diet including whole grains and plenty of fresh fruit and vegetables (at least five portions a day)
  • a diet high in complex vegetables and colorful fruit
  • tobacco cessation;
  • limit alcohol consumption;
  • lower blood pressures if elevated through diet and exercise;
  • decrease body fat (BMI);
  • increase daily activity to 30 minutes of any kind of exercise per day at least five times per week

A fairly recent emphasis is on the link between low-grade inflammation that hallmarks atherosclerosis and its possible interventions. C-reactive protein (CRP) is a common inflammatory marker that has been found to be present in increased levels in patients at risk for cardiovascular disease. Also osteoprotegerin which is involved with regulation of a key inflammatory transcription factor called NF-κB has been found to be a risk factor of cardiovascular disease and mortality. Studies have shown that Stem Cells have shown the ability to reduce inflammation.

 

Stem Cell Treatments for Heart Disease is an Option

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Related Articles Oleanolic Acid, a Novel Endothelin A Receptor Antagonist, Alleviated High Glucose-Induced Cardiomyocytes Injury. Am J Chin Med. 2018;46(6):1187-1201 Authors: Wu D, Zhang Q, Yu Y, Zhang Y, Zhang M, Liu Q, Zhang E, Li S, Song G Abstract Endothelin-1 (ET-1) and its receptor endothelin A receptor (ET[Formula: see text] have been shown to be upregulated in a high glucose environment, which increase the incidence of diabetes-related heart failure. Our previous study demonstrated that oleanolic acid (OA), a natural compound found in Chinese herbs had ET-1 antagonistic effects. We aimed to verify whether OA could ameliorate diabetes mellitus (DM)-induced injury in cardiomyocytes by reducing the antagonistic effects of the ET-1 pathway. For the induction of high glucose-related injury in cardiomyocytes, neonatal rat ventricular cardiomyocytes (NRVMs) were subjected to culture medium containing 25[Formula: see text]mM of glucose. Natriuretic peptide B (BNP), mitochondrial membrane potential (MMP) and cell surface area were measured to evaluate the severity of NRVMs injury. mRNA expression of ET-1 and ETA was determined using quantitative PCR. Moreover, a Ca[Formula: see text] influx assay was used to evaluate potential ETA antagonistic effects. Molecular docking of OA and ETA was performed using the Sulflex-Dock program. Human induced pluripotent stem cell (iPS-C)-derived cardiomyocytes and real time cell analysis system (RTCA) were used to verify the effect of OA on the ET-1 pathway. High glucose levels increased the expression of BNP at both mRNA and protein levels in cardiomyocytes. Moreover, cell surface area and MMP were also elevated in a high glucose environment. High glucose-induced injury in NRVMs was not reversible by hypoglycemic therapy. In addition, ETA was upregulated by high glucose treatment and levels could not be reduced by hypoglycemic treatment. The Ca[Formula: see text] influx assay on ETA/HEK293 cells showed that OA had a partial ETA antagonistic effect. Molecular docking approaches showed that OA was docked into the active site of ETA. Furthermore, functionality tests based on iPS-C and RTCA demonstrated that treatment with OA could reverse ET-1-induced alternation of beating rates and amplitude. Thus, OA could reverse high glucose-induced BNP upregulation, and increased both the cell area and MMP in NRVMs. High glucose-induced irreversible ETA upregulation is a major reason of continuous diabetes-related injury in cardiomyocytes. Treatment with OA had a protective effect on high glucose-induced injury in cardiomyocytes through a partial ETA antagonistic role. PMID: 30149760 [PubMed - in process]
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Related Articles Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid. Sci Rep. 2018 Aug 28;8(1):12960 Authors: Liu Q, Van Bortle K, Zhang Y, Zhao MT, Zhang JZ, Geller BS, Gruber JJ, Jiang C, Wu JC, Snyder MP Abstract 13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal differentiation in the context of cardiac development. This study further highlights the utility of human stem cells as an alternative system for investigating congenital diseases of newborns that arise as a result of maternal drug exposure during pregnancy. PMID: 30154523 [PubMed - in process]
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Related Articles Promotion of Cell-Based Therapy: Special Focus on the Cooperation of Mesenchymal Stem Cell Therapy and Gene Therapy for Clinical Trial Studies. Adv Exp Med Biol. 2018 Aug 29;: Authors: Golchin A, Rekabgardan M, Taheri RA, Nourani MR Abstract Regenerative medicine (RM) is a promising new field of medicine that has mobilized several new tools to repair or replace lost or damaged cells or tissues by stimulating natural regenerative mechanisms nearby cell and tissue-based therapy approaches. However, mesenchymal stem cell (MSC) based therapy has been shown to be safe and effective to a certain degree in multiple clinical trial studies (CTSs) of several diseases, in most MSC CTSs the efficacy of treatment has been reported low. Therefore, researchers have focused on efficacy enhancing of MSC to improve migratory and homing, survival, stemness, differentiation and other therapeutic applicable properties by using different approaches. Gene therapy is one of the experimental technique tools that uses genes to change cells for therapeutic and investigation purposes. In this study has been focused on genetically modified MSCs for use in RM with an emphasis on CTSs. We highlight the basic concept of genetic modifications and also discuss recent clinical studies aspects. Recently reviewed studies show that MSC therapy with assistant gene therapy can be used in cancer therapy, heart diseases, Fanconi anemia and several other diseases. PMID: 30155859 [PubMed - as supplied by publisher]
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Related Articles Hematopoietic stem cell transplantation alters susceptibility to pulmonary hypertension in Bmpr2-deficient mice. Pulm Circ. 2018 Oct-Dec;8(4):2045894018801642 Authors: Crosby A, Toshner MR, Southwood MR, Soon E, Dunmore BJ, Groves E, Moore S, Wright P, Ottersbach K, Bennett C, Guerrero J, Ghevaert C, Morrell NW Abstract Increasing evidence suggests that patients with pulmonary arterial hypertension (PAH) demonstrate abnormalities in the bone marrow (BM) and hematopoietic progenitor cells. In addition, PAH is associated with myeloproliferative diseases. We have previously demonstrated that low-dose lipopolysaccharide (LPS) is a potent stimulus for the development of PAH in the context of a genetic PAH mouse model of BMPR2 dysfunction. We hypothesized that the hematopoietic progenitor cells might be driving disease in this model. To test this hypothesis, we performed adoptive transfer of BM between wild-type (Ctrl) and heterozygous Bmpr2 null (Mut) mice. Sixteen weeks after BM reconstitution, mice were exposed to low-dose chronic LPS (0.5 mg/kg three times a week for six weeks). Mice underwent right heart catheterization and tissues were removed for histology. After chronic LPS dosing, Ctrl mice in receipt of Mut BM developed PAH, whereas Mut mice receiving Ctrl BM were protected from PAH. BM histology demonstrated an increase in megakaryocytes and there was an increase in circulating platelets in Ctrl mice receiving Mut BM. These findings demonstrate that the hematopoietic stem cell compartment is involved in the susceptibility to PAH in the Mut mouse. The results raise the possibility that hematopoietic stem cell transplantation might be a potential treatment strategy in genetic forms of PAH. PMID: 30160594 [PubMed]
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Related Articles Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential. Cardiovasc Res. 2018 Dec 01;114(14):1828-1842 Authors: van Mil A, Balk GM, Neef K, Buikema JW, Asselbergs FW, Wu SM, Doevendans PA, Sluijter JPG Abstract In the past few years, the use of specific cell types derived from induced pluripotent stem cells (iPSCs) has developed into a powerful approach to investigate the cellular pathophysiology of numerous diseases. Despite advances in therapy, heart disease continues to be one of the leading causes of death in the developed world. A major difficulty in unravelling the underlying cellular processes of heart disease is the extremely limited availability of viable human cardiac cells reflecting the pathological phenotype of the disease at various stages. Thus, the development of methods for directed differentiation of iPSCs to cardiomyocytes (iPSC-CMs) has provided an intriguing option for the generation of patient-specific cardiac cells. In this review, a comprehensive overview of the currently published iPSC-CM models for hereditary heart disease is compiled and analysed. Besides the major findings of individual studies, detailed methodological information on iPSC generation, iPSC-CM differentiation, characterization, and maturation is included. Both, current advances in the field and challenges yet to overcome emphasize the potential of using patient-derived cell models to mimic genetic cardiac diseases. PMID: 30169602 [PubMed - in process]
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Related Articles Cytokines as therapeutic agents and targets in heart disease. Cytokine Growth Factor Rev. 2018 Oct;43:54-68 Authors: Dubnika A, Manoukian MAC, Mohammadi MR, Parekh MB, Gurjarpadhye AA, Inayathullah M, Dubniks V, Lakey JRT, Rajadas J Abstract Cytokine therapies have emerged during the past decade as promising noninvasive treatments for heart disease. In general, current drug treatments are directed towards symptom control and prevention of disease progression; however, many agents also produce cause side effects that alter quality of life. Cytokine based therapies have the potential to reduce post-infarct heart failure and chronic ischemia by stimulating the proliferation and differentiation of endothelial cells and bone marrow hematopoietic stem cells and mobilizing these cells toward ischemic tissue. In turn, these mobilized cell populations contribute to myocardial regeneration. In contrast, over-expression of several cytokines has been linked to a variety of heart diseases; thus, therapies targeting and monitoring these cytokines are of great interest. Here we summarize results from clinical studies on cytokines as therapeutic agents or therapeutic targets in the treatment for heart disease as well as cytokines involved in the evolution of heart disease. PMID: 30170892 [PubMed - in process]
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Related Articles The role of GPCR signaling in cardiac Epithelial to Mesenchymal Transformation (EMT). Trends Cardiovasc Med. 2018 Aug 22;: Authors: Nebigil CG, Désaubry L Abstract Congenital heart disease is the most common birth defect, affecting 1.35 million newborns every year. Heart failure is a primary cause of late morbidity and mortality after myocardial infarction. Heart development is involved in several rounds of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET). Errors in these processes contribute to congenital heart disease, and exert deleterious effects on the heart and circulation after myocardial infarction. The identification of factors that are involved in heart development and disease, and the development of new approaches for the treatment of these disorders are of great interest. G protein coupled receptors (GPCRs) comprise 40% of clinically used drug targets, and their signaling are vital components of the heart during development, cardiac repair and in cardiac disease pathogenesis. This review focuses on the importance of EMT program in the heart, and outlines the newly identified GPCRs as potential therapeutic targets of reprogramming EMT to support cardiac cell fate during heart development and after myocardial infarction. More specifically we discuss prokineticin, serotonin, sphingosine-1-phosphate and apelin receptors in heart development and diseases. Further understanding of the regulation of EMT/MET by GPCRs during development and in the adult hearts can provide the following clinical exploitation of these pathways. PMID: 30172578 [PubMed - as supplied by publisher]
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Related Articles Building a new strategy for treating heart failure using Induced Pluripotent Stem Cells. J Cardiol. 2018 Dec;72(6):445-448 Authors: Miyagawa S, Sawa Y Abstract Although cell therapy using myoblasts, bone marrow cells, or other stem cells appears to improve functional recovery of the failing heart, mainly by cytokine paracrine effects, its effectiveness in severely damaged myocardium is limited, probably because there are too few residual myocytes to promote cytokine-induced angiogenesis. Recently, cardiogenic stem cells, such as c-kit-positive cells, were reported to generate cardiomyogenic lineages, and basic research experiments showed that implanting these cells, which can differentiate into cardiomyocytes, improves heart function. However, this functional recovery may have also mainly depended on cytokine paracrine effects, because the differentiation to cardiomyocytes in vivo was poor. In contrast, while Induced Pluripotent Stem Cell-derived cardiomyocytes have paracrine effects, they also have the potential to supply newly born myocytes that can function synchronously with the recipient myocardium as "mechanically working cells" in severely damaged myocardium. Thus, they could represent a "true" myocardial regeneration therapy that can actually regenerate severely damaged myocardium. In addition, iPS cells, especially disease-specific iPS cells, have other applications in regenerative medicine such as in drug screening. In this report, we present the state of basic research in the field of cardiac iPS cells. PMID: 30172684 [PubMed - in process]
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Related Articles New Insights into the Role of Exosomes in the Heart After Myocardial Infarction. J Cardiovasc Transl Res. 2018 Sep 02;: Authors: Li N, Rochette L, Wu Y, Rosenblatt-Velin N Abstract Intercellular communications play a pivotal role in several cardiac pathophysiological processes. One subtype of extracellular vesicles, so-called exosomes, became known as important intercellular communication mediators in the heart. Exosomes are lipid bilayer biological nanovesicles loaded with diverse proteins, lipids, and mRNAs/microRNAs. All major cardiac cell types can modulate recipient cellular function via the release of exosomes. After myocardial infarction (MI), exosomes, especially those secreted by different cardiac stem cells, have been shown to confer cardioprotective effects, activate regenerative signals, and participate into cardiac repair. In this review, we rapidly recall the biology of exosomes at the beginning. Then we summarize the exosomes secreted by different myocardial cells and their function in cardiac intercellular communication. At last, we discuss the role of these vesicles in cardiac repair after MI. PMID: 30173401 [PubMed - as supplied by publisher]
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Related Articles Coronary stents with inducible VEGF/HGF-secreting UCB-MSCs reduced restenosis and increased re-endothelialization in a swine model. Exp Mol Med. 2018 Sep 03;50(9):114 Authors: Chang HK, Kim PH, Kim DW, Cho HM, Jeong MJ, Kim DH, Joung YK, Lim KS, Kim HB, Lim HC, Han DK, Hong YJ, Cho JY Abstract Atherosclerotic plaques within the vasculature may eventually lead to heart failure. Currently, cardiac stenting is the most effective and least invasive approach to treat this disease. However, in-stent restenosis is a complex chronic side effect of stenting treatment. This study used coronary stents coated with stem cells secreting angiogenic growth factors via an inducible genome-editing system to reduce stent restenosis and induce re-endothelialization within the artery. The characteristics of the cells and their adhesion properties on the stents were confirmed, and the stents were transplanted into a swine model to evaluate restenosis and the potential therapeutic use of stents with stem cells. Restenosis was evaluated using optical coherence tomography (OCT), microcomputed tomography (mCT) and angiography, and re-endothelialization was evaluated by immunostaining after cardiac stent treatment. Compared to a bare metal stent (BMS) or a parental umbilical cord blood-derived mesenchymal stem cell (UCB-MSC)-coated stent, the stents with stem cells capable of the controlled release of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) successfully reduced restenosis within the stent and induced natural re-endothelialization. Furthermore, UCB-MSCs exhibited the ability to differentiate into endothelial cells in Matrigel, and HGF and VEGF improved this differentiation. Our study indicates that stents coated with UCB-MSCs secreting VEGF/HGF reduce the restenosis side effects of cardiac stenting with improved re-endothelialization. PMID: 30174328 [PubMed - in process]
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Related Articles Pericarditis in Patients With Chronic Graft-vs-Host Disease. Transplant Proc. 2018 Sep;50(7):2218-2222 Authors: Karakulska-Prystupiuk E, Basak G, Dwilewicz-Trojaczek J, Paluszewska M, Boguradzki P, Jędrzejczak W Abstract BACKGROUND: There are only a few cases of pericarditis complications following allogeneic bone marrow transplantation described in the literature and there are no data available on the risk and frequency of this condition. The aim of this study was to assess the frequency of exudative pericarditis complicating chronic graft-vs-host disease in allogeneic hematopoietic cell transplant recipients. METHODS: Retrospective analysis involved a group of 105 patients of the Outpatient Transplantation Service of the Department of Hematology, Medical University of Warsaw, who received transplants in the years 2010-2016 and were evaluated for the years 2014-2016. In this group, 50 patients suffered from chronic graft-vs-host disease (cGVHD), including 24 with moderate or severe disease. Cardiology parameters evaluated included electrocardiography, echocardiography, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systematic clinical follow-up. RESULTS: Pericarditis was diagnosed in 6 patients (aged 20-56 years) within 4 to 23 months after allogenic hematopoietic stem cell transplantation. All patients suffered from severe cGVHD with involvement of at least 2 organs but none had earlier history of heart disease. All patients had elevated NT-proBNP and demonstrated signs of heart insufficiency grade II or III according to the New York Heart Association. There were no major changes in electrocardiogram. Only 1 patient improved following glucocorticosteroids as monotherapy, while others required complex approaches including tacrolimus plus sirolimus, rituximab, and extracorporeal photopheresis. CONCLUSION: Late pericarditis may occur in up to 5% of allogenic hematopoietic stem cell transplantation survivors, primarily affecting patients with moderate and severe grade cGVHD. It requires escalation of immunosuppressive treatment but usually has favorable outcome. Early diagnosis may be achieved by systematic NT-proBNP testing and periodic echocardiograph evaluation. PMID: 30177139 [PubMed - indexed for MEDLINE]
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Related Articles Cardiac Stem Cell Characteristics in Physiological and Pathological Conditions. Curr Pharm Des. 2018 Sep 03;: Authors: Ozturk S, Elcin YM Abstract For nearly a century, the adult heart was considered as a post-mitotic organ. The discovery of a resident cardiac stem cell (CSC) population in the heart has dramatically undermined this notion with the support of encouraging preclinical and clinical studies aiming to regenerate the damaged heart after a myocardial infarction (MI). There are two ways to obtain CSCs for transplantation: Allogeneic and autologous sources. Autologous cells may be obtained from the patients' own tissue. Obtaining cells from diseased patients may contain a risk for altered stem cell characteristics. In addition to MI, these patients may also suffer from pathological conditions such as hypertension, diabetes mellitus, heart failure, congenital heart disease or cancer, which are known to alter CSC characteristics. It is also known that physiological conditions such as aging and death affect CSC functions in the heart. Our knowledge about the CSC characteristics in various physiological and pathological conditions may shed light on our opinion about the regenerative capacity and biological activity of these cells in these situations. Defining these properties may guide the researchers and clinicians for choosing and obtaining the most qualified CSC populations for cardiac regenerative medicine therapies. The purpose of this review is to describe the alterations in CSC characteristics in various physiological and pathological conditions. PMID: 30179126 [PubMed - as supplied by publisher]
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Related Articles A review of application of stem cell therapy in the management of congenital heart disease. J Matern Fetal Neonatal Med. 2018 Oct 01;:1-9 Authors: Ghafarzadeh M, Namdari P, Tarhani M, Tarhani F Abstract Research on stem cells has been rapidly growing with impressive breakthroughs. Although merely a few of the laboratory researches have successfully transited to the clinical trial phase, the application of stem cells as a therapeutic option for some currently incapacitating diseases hold fascinating potentials. This review emphasis the various opportunities for the application of stem cell in the treatment of fetal diseases. First, we provide a brief commentary on the common stem cell strategy used in the treatment of congenital anomalies, thereafter we discuss how stem cell is being used in the management of some fetal disorders. PMID: 30185081 [PubMed - as supplied by publisher]
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Related Articles Mesenchymal stem cell and bone marrow mononuclear cell therapy for cardiomyopathy: From bench to bedside. J Cell Biochem. 2019 Jan;120(1):45-55 Authors: Dolati S, Yousefi M, Mahdipour M, Afrasiabi Rad A, Pishgahi A, Nouri M, Jodati AR Abstract To date, stem cell-based therapies for cardiac diseases have not achieved any significant clinical accomplishment. Globally, numerous patients are currently treated with autologous stem cells. The safety and practicality of this technique have been well-examined, its disadvantages have been recognized, and many trials have been proposed. Inadequate description of the implemented cell types, a variety of cell-handling proficiencies, and concerning factors related to autologous stem cells have been known as the central elements restricting the approval of cell-based therapies. The idea that bone marrow (BM)-derived cells could be applied to regenerate and cure damage in various organs is the basis for bone marrow mononuclear cell (BMMNC) therapy for heart disease. Mesenchymal stem cells (MSCs) are a part of the BMMNCs; on one hand, they have the capability to differentiate into various tissues, and, on the other, their immunomodulatory effects have been considered and clinically confirmed in different experiments. In this review, we summarize the knowledge obtained by trials in which mesenchymal cell-based therapy has been practiced. Furthermore, we accentuate the developments in the purification and lineage specification of MSCs as well as BMMNCs that have influenced the progress of future stem cell-based therapies with special attention on cardiovascular disease. PMID: 30191597 [PubMed - in process]
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Related Articles Mesenchymal Stem Cell Therapy For Ischemic Heart Disease: Advances And Challenges. Curr Pharm Des. 2018 Sep 13;: Authors: Konoplyannikov M, Kotova S, Baklaushev V, Konoplyannikov A, Kalsin V, Timashev P, Troitsky A Abstract Ischemic heart disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect, manipulating their cardiomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June, 2018. PMID: 30209995 [PubMed - as supplied by publisher]
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Related Articles Effects of trans-endocardial delivery of bone marrow-derived CD133+ cells on angina and quality of life in patients with refractory angina: A sub-analysis of the REGENT-VSEL trial. Cardiol J. 2018;25(4):521-529 Authors: Jadczyk T, Ciosek J, Michalewska-Wludarczyk A, Szot W, Parma Z, Ochala B, Markiewicz M, Rychlik W, Kostkiewicz M, Gruszczynska K, Blach A, Dzierzak-Mietla M, Rzeszutko L, Partyka L, Zasada W, Smolka G, Pawlowski T, Jedrzejek M, Starek Z, Plens K, Ochala A, Tendera M, Wojakowski W Abstract BACKGROUND: The REGENT-VSEL trial demonstrated a neutral effect of transendocardial injection of autologous bone marrow (BM)-derived CD133+ in regard to myocardial ischemia. The current sub-analysis of the REGENT VSEL trial aims to assess the effect stem cell therapy has on quality of life (QoL) in patients with refractory angina. METHODS: Thirty-one patients (63.0 ± 6.4 years, 70% male) with recurrent CCS II-IV angina, despite optimal medical therapy, enrolled in the REGENT-VSEL single center, randomized, double-blinded, and placebo-controlled trial. Of the 31 patients, 16 individuals were randomly assigned to the active stem cell group and 15 individuals were randomly assigned to the placebo group on a 1:1 basis. The inducibility of ischemia, (≥ one myocardial segment) was confirmed for each patient using Tc-99m SPECT. QoL was measured using the Seattle Angina Questionnaire. Each patient completed the questionnaire prior to treatment and at the time of their outpatient follow-up visits at 1, 4, 6, and 12 months after cell/placebo treatment. RESULTS: The main finding of the REGENT-VSEL trial sub-analysis was that transendocardial injection of autologous BM-derived CD133+ stem cells in patients with chronic refractory angina did not show significant improvement in QoL in comparison to the control group. Moreover, there was no significant difference between cell therapy and placebo in a number of patients showing improvement of at least 1 Canadian Cardiovascular Society class during the follow-up period. CONCLUSIONS: Intra-myocardial delivery of autologous CD133+ stem cells is safe and feasible but does not show a significant improvement in the QoL or angina pectoris symptoms in patients with chronic myocardial ischemia. PMID: 30211929 [PubMed - in process]
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Related Articles Long-Term Engraftment (16 Years) of Myoblasts in a Human Infarcted Heart. Stem Cells Transl Med. 2018 Oct;7(10):705-708 Authors: Crahès M, Bories MC, Viquin JT, Marolleau JP, Desnos M, Larghero J, Soulat G, Bruneval P, Hagège AA, Menasché P Abstract We report the case of a patient who had undergone injections of myoblasts in an infarct area 16 years before being referred for heart transplantation. The pathological examination of the explanted heart found persisting myotubes embedded in fibrosis. This finding supports the ability of myoblasts to survive in harsh environments, which can make them appealing candidates for transplantation in diseases requiring supply of new myogenic cells. Stem Cells Translational Medicine 2018;7:705-708. PMID: 30211981 [PubMed - in process]
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Related Articles Linking cell function with perfusion: insights from the transcatheter delivery of bone marrow-derived CD133+ cells in ischemic refractory cardiomyopathy trial (RECARDIO). Stem Cell Res Ther. 2018 Sep 14;9(1):235 Authors: Bassetti B, Carbucicchio C, Catto V, Gambini E, Rurali E, Bestetti A, Gaipa G, Belotti D, Celeste F, Parma M, Righetti S, Biava L, Arosio M, Bonomi A, Agostoni P, Scacciatella P, Achilli F, Pompilio G Abstract BACKGROUND: Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133+ cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function. METHODS: In the phase I "Endocavitary Injection of Bone Marrow Derived CD133+ Cells in Ischemic Refractory Cardiomyopathy" (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ≤ 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations. RESULTS: Patients were treated safely with a mean number of 6.57 ± 3.45 ×  106 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 ± 8.6 to 13.8 ± 7.8, p = 0.05) and difference scores (from 12.0 ± 5.3 to 6.1 ± 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 ± 2.2 to 4.0 ± 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p ≤ 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = - 0.79, p = 0.01) and IL-6 (r = - 0.76, p = 0.02). CONCLUSION: Results of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02059681 . Registered 11 February 2014. PMID: 30217223 [PubMed - in process]
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Related Articles Chitosan/silk fibroin modified nanofibrous patches with mesenchymal stem cells prevent heart remodeling post-myocardial infarction in rats. Acta Biomater. 2018 Oct 15;80:154-168 Authors: Chen J, Zhan Y, Wang Y, Han D, Tao B, Luo Z, Ma S, Wang Q, Li X, Fan L, Li C, Deng H, Cao F Abstract Poor functional survival of the engrafted stem cells limits the therapeutic efficacy of stem-cell-based therapy for myocardial infarction (MI). Cardiac patch-based system for cardiac repair has emerged as a potential regenerative strategy for MI. This study aimed to design a cardiac patch to improve the retention of the engrafted stem cells and provide mechanical scaffold for preventing the ventricular remodeling post-MI. The patches were fabricated with electrospinning cellulose nanofibers modified with chitosan/silk fibroin (CS/SF) multilayers via layer-by-layer (LBL) coating technology. The patches engineered with adipose tissue-derived mesenchymal stem cells (AD-MSCs) (cell nano-patch) were adhered to the epicardium of the infarcted region in rat hearts. Bioluminescence imaging (BLI) revealed higher cell viability in the cell nano-patch group compared with the intra-myocardial injection group. Echocardiography demonstrated less ventricular remodeling in cell nano-patch group, with a decrease in the left ventricular end-diastolic volume and left ventricular end-systolic volume compared with the control group. Additionally, left ventricular ejection fraction and fractional shortening were elevated after cell nano-patch treatment compared with the control group. Histopathological staining demonstrated that cardiac fibrosis and apoptosis were attenuated, while local neovascularization was promoted in the cell nano-patch group. Western blot analysis illustrated that the expression of biomarkers for myocardial fibrosis (TGF-β1, P-smad3 and Smad3) and ventricular remodeling (BNP, β-MHC: α-MHC ratio) were decreased in cell nano patch-treated hearts. This study suggests that CS/SF-modified nanofibrous patches promote the functional survival of engrafted AD-MSCs and restrain ventricular remodeling post-MI through attenuating myocardial fibrosis. STATEMENT OF SIGNIFICANCE: First, the nanofibrous patches fabricated from the electrospun cellulose nanofibers could mimic the natural extracellular matrix (ECM) of hearts to improve the microenvironment post-MI and provide three dimensional (3D) scaffolds for the engrafted AD-MSCs. Second, CS and SF which have exhibited excellent properties in previous tissue engineering research, such as nontoxicity, biodegradability, anti-inflammatory, strong hydrophilic nature, high cohesive strength, and intrinsic antibacterial properties further optimized the biocompatibility of the nanofibrous patches via LBL modification. Finally, the study revealed that beneficial microenvironment and biomimetic ECM improve the retention and viability of the engrafted AD-MSCs and the mechanical action of the cell nano-patches for the expanding ventricular post-MI leads to suppression of HF progression by inhibition of ventricular remodeling. PMID: 30218777 [PubMed - in process]
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Related Articles Angiogenic lncRNAs: A potential therapeutic target for ischaemic heart disease. Life Sci. 2018 Oct 15;211:157-171 Authors: Xu ZM, Huang F, Huang WQ Abstract Long noncoding RNAs (LncRNAs) are involved in biological processes and the pathology of diseases and represent an important biomarker or therapeutic target for disease. Emerging evidence has suggested that lncRNAs modulate angiogenesis by regulating the angiogenic cell process-including vascular endothelial cells (VECs); stem cells, particularly bone marrow-derived stem cells, endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs); and vascular smooth muscle cells (VSMCs)-and participating in ischaemic heart disease (IHD). Therapeutic angiogenesis as an alternative therapy to promote coronary collateral circulation has been demonstrated to significantly improve the prognosis and quality of life of patients with IHD in past decades. Therefore, lncRNAs are likely to represent a novel therapeutic target for IHD through regulation of the angiogenesis process. This review summarizes the classification and functions of lncRNAs and their roles in regulating angiogenesis and in IHD, in the context of an overview of therapeutic angiogenesis in clinical trials. PMID: 30219334 [PubMed - indexed for MEDLINE]
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Related Articles Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease. Orphanet J Rare Dis. 2018 Sep 17;13(1):152 Authors: Vu M, Li R, Baskfield A, Lu B, Farkhondeh A, Gorshkov K, Motabar O, Beers J, Chen G, Zou J, Espejo-Mojica AJ, Rodríguez-López A, Alméciga-Díaz CJ, Barrera LA, Jiang X, Ory DS, Marugan JJ, Zheng W Abstract BACKGROUND: Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes β-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD. RESULTS: We generated induced pluripotent stem cells (iPSCs) from two TSD patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. The Tay-Sachs disease NSCs were then used to evaluate the therapeutic effects of enzyme replacement therapy (ERT) with recombinant human Hex A protein and two small molecular compounds: hydroxypropyl-β-cyclodextrin (HPβCD) and δ-tocopherol. Using this disease model, we observed reduction of lipid accumulation by employing enzyme replacement therapy as well as by the use of HPβCD and δ-tocopherol. CONCLUSION: Our results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. The enzyme replacement therapy with recombinant Hex A protein and two small molecules (cyclodextrin and tocopherol) significantly ameliorated lipid accumulation in the Tay-Sachs disease cell model. PMID: 30220252 [PubMed - in process]
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Related Articles Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial. Lancet Oncol. 2018 Oct;19(10):1328-1337 Authors: Anderson RA, Remedios R, Kirkwood AA, Patrick P, Stevens L, Clifton-Hadley L, Roberts T, Hatton C, Kalakonda N, Milligan DW, McKay P, Rowntree C, Scott FM, Johnson PWM Abstract BACKGROUND: Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation. METHODS: We recruited female participants from the randomised phase 3 RATHL trial, aged 18-45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB-IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0-3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327. FINDINGS: Between Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3-17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07-0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37-0·65; p<0·0001). INTERPRETATION: Reduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes. FUNDING: Medical Research Foundation and Cancer Research UK. PMID: 30220622 [PubMed - in process]
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Related Articles Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: Functional assessment using in vitro radionuclide uptake assay. Int J Cardiol. 2018 Oct 15;269:229-234 Authors: Nose N, Werner RA, Ueda Y, Günther K, Lapa C, Javadi MS, Fukushima K, Edenhofer F, Higuchi T Abstract BACKGROUND: Recent developments in cellular reprogramming technology enable the production of virtually unlimited numbers of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Although hiPSC-CM share various characteristic hallmarks with endogenous cardiomyocytes, it remains a question as to what extent metabolic characteristics are equivalent to mature mammalian cardiomyocytes. Here we set out to functionally characterize the metabolic status of hiPSC-CM in vitro by employing a radionuclide tracer uptake assay. MATERIAL AND METHODS: Cardiac differentiation of hiPSC was induced using a combination of well-orchestrated extrinsic stimuli such as WNT activation (by CHIR99021) and BMP signalling followed by WNT inhibition and lactate based cardiomyocyte enrichment. For characterization of metabolic substrates, dual tracer uptake studies were performed with 18F‑2‑fluoro‑2‑deoxy‑d‑glucose (18F-FDG) and 125I‑β‑methyl‑iodophenyl‑pentadecanoic acid (125I-BMIPP) as transport markers of glucose and fatty acids, respectively. RESULTS: After cardiac differentiation of hiPSCs, in vitro tracer uptake assays confirmed metabolic substrate shift from glucose to fatty acids that was comparable to those observed in native isolated human cardiomyocytes. Immunostaining further confirmed expression of fatty acid transport and binding proteins on hiPSC-CM. CONCLUSIONS: During in vitro cardiac maturation, we observed a metabolic shift to fatty acids, which are known as a main energy source of mammalian hearts, suggesting hi-PSC-CM as a potential functional phenotype to investigate alteration of cardiac metabolism in cardiac diseases. Results also highlight the use of available clinical nuclear medicine tracers as functional assays in stem cell research for improved generation of autologous differentiated cells for numerous biomedical applications. PMID: 30224033 [PubMed - in process]
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Related Articles Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes Promotes Repair in Ischemic Myocardium. J Cardiovasc Transl Res. 2018 Oct;11(5):420-428 Authors: Ju C, Shen Y, Ma G, Liu Y, Cai J, Kim IM, Weintraub NL, Liu N, Tang Y Abstract Our previous study demonstrated the beneficial effects of exosomes secreted by cardiac mesenchymal stem cells (C-MSC-Exo) in protecting acute ischemic myocardium from reperfusion injury. Here, we investigated the effect of exosomes from C-MSC on angiogenesis in ischemic myocardium. We intramyocardially injected C-MSC-Exo or PBS into the infarct border zone after induction of acute mouse myocardial infarction (MI). We observed that hearts treated with C-MSC-Exo exhibit improved cardiac function compared to control hearts treated with PBS at one month after MI. Capillary density and Ki67-postive cells were significantly higher following treatment with C-MSC-Exo as compared with PBS. Moreover, C-MSC-Exo treatment increased cardiomyocyte proliferation in infarcted hearts. In conclusion, intramyocardial delivery of C-MSC-Exo after myocardial infarction enhances cardiac angiogenesis, promotes cardiomyocyte proliferation, and preserves heart function. C-MSC-Exo constitute a novel form of cell-free therapy for cardiac repair. PMID: 30232729 [PubMed - in process]
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Related Articles Cardiac Extracellular Matrix Modification as a Therapeutic Approach. Adv Exp Med Biol. 2018;1098:131-150 Authors: Hall ML, Ogle BM Abstract The cardiac extracellular matrix (cECM) is comprised of proteins and polysaccharides secreted by cardiac cell types, which provide structural and biochemical support to cardiovascular tissue. The roles of cECM proteins and the associated family of cell surface receptor, integrins, have been explored in vivo via the generation of knockout experimental animal models. However, the complexity of tissues makes it difficult to isolate the effects of individual cECM proteins on a particular cell process or disease state. The desire to further dissect the role of cECM has led to the development of a variety of in vitro model systems, which are now being used not only for basic studies but also for testing drug efficacy and toxicity and for generating therapeutic scaffolds. These systems began with 2D coatings of cECM derived from tissue and have developed to include recombinant ECM proteins, ECM fragments, and ECM mimics. Most recently 3D model systems have emerged, made possible by several developing technologies including, and most notably, 3D bioprinting. This chapter will attempt to track the evolution of our understanding of the relationship between cECM and cell behavior from in vivo model to in vitro control systems. We end the chapter with a summary of how basic studies such as these have informed the use of cECM as a direct therapy. PMID: 30238369 [PubMed - in process]
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Related Articles Extracellular Matrix for Myocardial Repair. Adv Exp Med Biol. 2018;1098:151-171 Authors: Dziki JL, Badylak SF Abstract Multiple strategies have been investigated to restore functional myocardium following injury or disease including the local administration of cytokines or chemokines, stem/progenitor cell therapy, mechanical circulatory support, pharmacologic use, and the use of inductive biomaterials. The use of xenogeneic biologic scaffolds composed of extracellular matrix (ECM) has been shown to facilitate functional restoration of several tissues and organs including the esophagus, skeletal muscle, skin, and myocardium, among others. The present chapter describes the current understanding of specific components of biologic scaffolds composed of ECM, the mechanisms by which ECM bioscaffolds promote constructive cardiac remodeling after injury, determinants of remodeling outcome, and the versatility of ECM as a potential cardiac therapeutic. PMID: 30238370 [PubMed - in process]
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Related Articles Clinical Trial Design for Investigational Cardio-Regenerative Therapy. Adv Exp Med Biol. 2018;1098:199-211 Authors: Raval AN Abstract Human trials of cardio-regenerative biologic therapies are being performed worldwide to address a growing, unmet need for durable treatments of cardiovascular disease. A well-constructed clinical trial design for these novel therapies requires careful attention to defining a clear hypothesis, a patient population, and anticipated outcomes. The scope of screening, method of randomization, blinding approach, data monitoring, and statistical analysis plan are the foundational elements that must be addressed in any clinical trial. Although the experience of human trials involving extracellular matrix constructs for cardiovascular disease treatment is limited, numerous lessons have been learned in the field of cell therapy that are translatable across all biologic treatment options. Future progress in this field may include testing combinations of cells, gene-transfer agents, and matrix and identifying treatment responders versus nonresponders. PMID: 30238373 [PubMed - in process]
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Related Articles Cell Sheet-Based Vascularized Myocardial Tissue Fabrication. Eur Surg Res. 2018;59(3-4):276-285 Authors: Komae H, Ono M, Shimizu T Abstract BACKGROUND: The development of regenerative medicine in recent years has been remarkable as tissue engineering technology and stem cell research have advanced. The ultimate goal of regenerative medicine is to fabricate human organs artificially. If fabricated organs can be transplanted medically, it will be the innovative treatment of diseases for which only donor organ transplantation is the definitive therapeutic method at present. SUMMARY: Our group has reported successful fabrication of thick functional myocardial tissue in vivo and in vitro by using cell sheet engineering technology which requires no scaffolds. Thick myocardial tissue can be fabricated by stacking cardiomyocyte sheets on the vascular bed every 24 h, so that a vascular network can be formed within the myocardial graft. We call this procedure a multi-step transplantation procedure. After human-induced pluripotent stem cells were discovered and human cardiomyocytes became available, a thick, macroscopically pulsate human myocardial tissue was successfully constructed by using a multi-step transplantation procedure. Furthermore, our group succeeded in fabricating functional human myocardial tissue which can generate pressure. Here, we present our way of fabricating human myocardial tissue by means of cell sheet engineering technology. Key Messages: Our group succeeded in fabricating thick, functional human myocardium which can generate pulse pressure. However, there are still a few problems to be solved until clinically functional human cardiac tissue or a whole heart can be fabricated. Research on myocardial regeneration progresses at such a pace that we believe the products of this research will save many lives in the near future. PMID: 30244251 [PubMed - in process]
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Related Articles Thymopoiesis in Pre- and Post-Hematopoietic Stem Cell Transplantation. Front Immunol. 2018;9:1889 Authors: da Rocha LKA, Freschi de Barros S, Bandeira F, Bollini A, Testa LHA, Simione AJ, Souza MOE, Zanetti LP, de Oliveira LCS, Dos Santos ACF, de Souza MP, Colturado VAR, Kalil J, Machado CM, Guilherme L Abstract Hematopoietic stem cell transplantation (HSCT) is an important therapeutic option for some hematological diseases. However, patients who undergo HSCT acquire a state of immunodeficiency that causes significant mortality. Reconstitution of thymic function is needed to support the immune system. One way to measure thymic function is through T-cell receptor excision circle (TREC) quantification. TRECs are generated by T-cell receptor gene rearrangements during T-cell maturation in the thymus and represent a reliable marker for thymic output. In this study, we aimed to assess aging and malignant hematological diseases as two important factors that may influence thymic output before HSCT. We observed that patients before HSCT presented signal joint TREC (sjTREC) numbers lower than 606.55 copies/μg DNA (low values) compared with healthy individuals, with an odds ratio (OR) of 12.88 [95% confidence interval (CI): 5.26-31.53; p < 0.001]. Our results showed that a group of older individuals (≥50 years old), comprising both healthy individuals and patients, had an OR of 10.07 (95% CI: 2.80-36.20) for low sjTREC values compared with younger individuals (≤24 years old; p < 0.001). Multiple logistic regression analysis confirmed that both older age (≥50 years old) and malignant hematological diseases and their treatments were important and independent risk factors related to thymic function impairment (p < 0.001). The median sjTREC value for patients of all ages was significantly lower than the sjTREC median for the subgroup of older healthy individuals (≥50 years old; p < 0.001). These data suggested that patients before HSCT and healthy individuals exhibited age-dependent thymic impairment, and that prior treatment for hematological diseases may exacerbate aging-related deterioration of natural thymic function. Furthermore, we analyzed these patients 9 months post-HSCT and compared patients who underwent autologous HSCT with those who underwent allogeneic HSCT. Both groups of patients achieved sjTREC copy numbers similar to those of healthy individuals. We did not find a close relationship between impaired thymic function prior to HSCT and worse thymic recovery after HSCT. PMID: 30245685 [PubMed - in process]
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Related Articles Promising utilization areas of therapeutic plasmapheresis in cardiovascular surgery practice. Transfus Apher Sci. 2018 Sep 18;: Authors: Durdu MS, Cakici M, Gumus F, Deniz GC, Bozdag SC, Ozcinar E, Yaman ND, Ilhan O, Ucanok K Abstract OBJECTIVE: Apheresis is performed for treatment of numerous diseases by removing auto-antibodies, antigen-antibody complexes, allo-antibodies, paraproteins, non-Ig proteins, toxins, exogenous poisons. In current study, we present our experience of using therapeutic plasma exchange (TPE) in patients with different types of clinical scenarios. METHODS: Between January 2013 and May 2016, we retrospectively presented the results of 64 patients in whom postoperative TPE was performed in ICU setting after cardiac surgery. Patients were grouped into four as; 1-sepsis (n = 26), 2-hepatorenal syndrome(n = 24), 3-antibody mediated rejection(AMR) following heart transplantation(n = 4) and 4-right heart failure(RHF) after left ventricular asist device(LVAD)(n = 10). Hemodynamic parameters were monitored constantly, pre- and post-procedure peripheral blood tests including renal and liver functions and daily complete blood count (CBC), sedimentation, C-reactive protein and procalcitonin (ng/ml) levels were studied. RESULTS: The mean age was 61 ± 17.67 years old and 56.25% (n = 36) were male. Mean Pre TPE left ventricular ejection fraction (LVEF) (%), central venous pressure (CVP)(mmHg) pulmonary capillary wedge pressure (PCWP)(mmHg) and pulmonary arterial pressure (PAP)(mmHg) were measured as 41.8 ± 8.1, 15.5 ± 4.4, 17.3 ± 3.24 and 39.9 ± 5.4, respectively. Procalcitonin (ng/ml) level of patients undergoing TPE due to sepsis was significantly reduced from 873 ± 401 ng/ml to 248 ± 132 ng/ml. Seventeen (26.5%) patients died in hospital during treatment, mean length of intensive care unit (ICU) stay(days) was 13.2 ± 5.1. CONCLUSION: This study shows that TEP is a safe and feasible treatment modality in patients with different types of complications after cardiac surgery and hopefully this study will lead to new utilization areas. PMID: 30249533 [PubMed - as supplied by publisher]
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Related Articles Effectiveness of endothelial progenitor cell culture under microgravity for improved angiogenic potential. Sci Rep. 2018 Sep 24;8(1):14239 Authors: Hagiwara H, Higashibata A, Ogawa S, Kanazawa S, Mizuno H, Tanaka R Abstract Endothelial progenitor cell (EPC) transplantation is beneficial for ischemic diseases such as critical limb ischemia and ischemic heart disease. The scarcity of functional EPCs in adults is a limiting factor for EPC transplantation therapy. The quality and quantity culture (QQc) system is an effective ex vivo method for enhancing the number and angiogenic potential of EPCs. Further, microgravity environments have been shown to enhance the functional potential of stem cells. We therefore hypothesized that cells cultured with QQc under microgravity may have enhanced functionality. We cultured human peripheral blood mononuclear cells using QQc under normal (E), microgravity (MG), or microgravity followed by normal (ME) conditions and found that ME resulted in the most significant increase in CD34+ and double positive Dil-Ac-LDL-FITC-Ulex-Lectin cells, both EPC markers. Furthermore, angiogenic potential was determined by an EPC-colony forming assay. While numbers of primitive EPC-colony forming units (pEPC-CFU) did not change, numbers of definitive EPC-CFU colonies increased most under ME conditions. Gene-expression profiling also identified increases in angiogenic factors, including vascular endothelial growth factor, under MG and ME conditions. Thus, QQc along with ME conditions could be an efficient system for significantly enhancing the number and angiogenic potential of EPCs. PMID: 30250055 [PubMed - in process]
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Related Articles Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Transl Med. 2018 Dec;7(12):857-866 Authors: Lalu MM, Mazzarello S, Zlepnig J, Dong YYR, Montroy J, McIntyre L, Devereaux PJ, Stewart DJ, David Mazer C, Barron CC, McIsaac DI, Fergusson DA Abstract Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating both acute myocardial infarction (AMI) and ischemic heart failure (IHF). However, the safety profile and efficacy of MSC therapy is not well-known. We conducted a systematic review of clinical trials that evaluated the safety or efficacy of MSCs for AMI or IHF. Embase, PubMed/Medline, and Cochrane Central Register of Controlled Trials were searched from inception to September 27, 2017. Studies that examined the use of MSCs administered to adults with AMI or IHF were eligible. The Cochrane risk of bias tool was used to assess bias of included studies. The primary outcome was safety assessed by adverse events and the secondary outcome was efficacy which was assessed by mortality and left ventricular ejection fraction (LVEF). A total of 668 citations were reviewed and 23 studies met eligibility criteria. Of these, 11 studies evaluated AMI and 12 studies evaluated IHF. There was no association between MSCs and acute adverse events. There was a significant improvement in overall LVEF in patients who received MSCs (SMD 0.73, 95% CI 0.24-1.21). No significant difference in mortality was noted (Peto OR 0.68, 95% CI 0.38-1.22). Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe. There is a need for a well-designed adequately powered randomized control trial (with rigorous adverse event reporting and evaluations of cardiac function) to further establish a clear risk-benefit profile of MSCs. Stem Cells Translational Medicine 2018;7:857-866. PMID: 30255989 [PubMed - in process]
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Related Articles Deletion of SMARCA4 impairs alveolar epithelial type II cells proliferation and aggravates pulmonary fibrosis in mice. Genes Dis. 2017 Dec;4(4):204-214 Authors: Peng D, Si D, Zhang R, Liu J, Gou H, Xia Y, Tian D, Dai J, Yang K, Liu E, Shi Y, Lu QR, Zou L, Fu Z Abstract Alveolar epithelial cells (AECs) injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis (PF). Nevertheless, the exact mechanisms regulating the regeneration of AECs post-injury still remain unclear. SMARCA4 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF, which is essential for kidney and heart fibrosis. We investigates SMARCA4 function in lung fibrosis by establishing PF mice model with bleomycin firstly and found that the expression of SMARCA4 was mainly enhanced in alveolar type II (ATII) cells. Moreover, we established an alveolar epithelium-specific SMARCA4-deleted SP-C-rtTA/(tetO) 7 -Cre/SMARCA4 f/f mice (SOSM4 Δ/Δ ) model, as well as a new SMARCA4-deleted alveolar type II (ATII)-like mle-12 cell line. We found that the bleomycin-induced PF was more aggressive in SOSM4 Δ/Δ mice. Also, the proliferation of ATII cells was decreased with the loss of SMARCA4 in vivo and in vitro. In addition, we observed increased proliferation of ATII cells accompanied by abnormally high expression of SMARCA4 in human PF lung sections. These data uncovered the indispensable role of SMARCA4 in the proliferation of ATII cells, which might affect the progression of PF. PMID: 30258924 [PubMed]
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Related Articles Sustained Release of IGF-1 by 3D Mesoporous Scaffolds Promoting Cardiac Stem Cell Migration and Proliferation. Cell Physiol Biochem. 2018;49(6):2358-2370 Authors: Sun Y, Han X, Wang X, Zhu B, Li B, Chen Z, Ma G, Wan M Abstract BACKGROUND/AIMS: C-kit-positive cardiac stem cells (CSCs) may have potential as a treatment for cardiovascular disease. However, the low survival rates of c-kit-positive CSCs present a major challenge during the transplantation process. METHODS: The hierarchical structure of the 3D cell scaffold was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and N2 adsorption-desorption isotherms. Analyses of the proliferation and migration performances of the IGF-1 scaffold on c-kit-positive CSCs were conducted by experiments including QuantiT PicoGreen dsDNA and transwell assays. RESULTS: In this study, we synthesized for the first time a novel hierarchical macro-mesoporous silica material (denoted MS15-c) in a one-pot procedure for the release of insulin-like growth factor-1 (IGF-1) and a three-dimensional (3D) cell scaffold. Both macropores and mesopores were visible in MS15-c and enabled the sustained release of IGF-1, extending its half-life and enhancing CSC proliferation and migration. Proliferation and migration were detected by QuantiT PicoGreen dsDNA and transwell assays, respectively. Moreover, an in vivo experiment was conducted to detect heart function with the addition of MS15-c. The new strategy proposed in this paper may extend the bio-applications of 3D cell scaffolds, thus permitting the sustained release of growth factors and efficient promotion of cell proliferation. CONCLUSION: This work successfully demonstrated an effective strategy for the construction of MS15-c cell scaffolds with hierarchical macro-mesoporous structures. The macro-mesoporous structures gave cell scaffolds the ability to release a growth factor to facilitate cell growth, while the scaffold structure promoted cell proliferation. PMID: 30261486 [PubMed - indexed for MEDLINE]
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Related Articles Apheresis on aged patients/donors with complicated backgrounds like ischemic heart disease, arrhythmia, and others. Transfus Apher Sci. 2018 Oct;57(5):619-622 Authors: Yokohama A, Yokote K, Maruhashi T Abstract Peripheral blood stem cells (PBSCs) are currently one of the most important stem cell sources for hematopoietic stem cell transplantation as well as cell therapy for ischemic heart disease or critical limb ischemia. Thus, it is sometimes necessary to collect autologous PBSCs from donors who have comorbidities. In terms yield, a sufficient number of PBSCs can be collected from donors with comorbidities for performing cell therapy if their age is < 60 years or up to a maximum of 70 years, although the number of PBSCs collected from older donors would probably be lower than that obtained from younger donors. On the other hand, granulocyte colony-stimulating factor (G-CSF) administration sometimes results in severe adverse events (AEs), such as ischemic heart disease and vascular thrombosis. Therefore, it is very important to perform strict medical check-ups according to the standards for donor operations in each country before apheresis. The apheresis procedure and G-CSF administration should be performed after administering the appropriate treatment. There is very less information available regarding AEs related to citrate administration during apheresis in aged donors with complicated medical histories. Medical staff should have knowledge of the electrocardiogram (ECG) QTc prolongation that occurs during apheresis owing to hypocalcemia caused by citrate administration, necessitating electrocardiographic monitoring of patients. Calcium should be administered during apheresis to prevent citrate related symptoms. PMID: 30262215 [PubMed - in process]
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Related Articles Dioxin and AHR impairs mesoderm gene expression and cardiac differentiation in human embryonic stem cells. Sci Total Environ. 2019 Feb 15;651(Pt 1):1038-1046 Authors: Fu H, Wang L, Wang J, Bennett BD, Li JL, Zhao B, Hu G Abstract Dioxin and dioxin-related polychlorinated biphenyls are potent toxicants with association with developmental heart defects and congenital heart diseases. However, the underlying mechanism of their developmental toxicity is not fully understood. Further, different animals show distinct susceptibility and phenotypes after exposure, suggesting possible species-specific effects. Using a human embryonic stem cell (ESC) cardiomyocyte differentiation model, we examined the impact, susceptible window, and dosage of 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin (TCDD) on human cardiac development. We showed that treatment of human ESCs with TCDD at the ESC stage inhibits cardiomyocyte differentiation, and the effect is largely mediated by the aryl hydrocarbon receptor (AHR). We further identified genes that are differentially expressed after TCDD treatment by RNA-sequencing, and genomic regions that are occupied by AHR by chromatin immunoprecipitation and high-throughput sequencing. Our results support the model that TCDD impairs human ESC cardiac differentiation by promoting AHR binding and repression of key mesoderm genes. More importantly, our study demonstrates the toxicity of dioxin in human embryonic development and uncovered a novel mechanism by which dioxin and AHR regulates lineage commitment. It also illustrates the power of ESC-based models in the systematic study of developmental toxicology. PMID: 30266049 [PubMed - indexed for MEDLINE]
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Related Articles Changes in coexpression of pericytes and endogenous cardiac progenitor cells from heart development to disease state. Eur Heart J. 2018 Aug 28;39(Suppl 1): Authors: Lerman DA, Diaz M, Peault B Abstract Introduction: Focussing on the potential role of cardiovascular cell therapy, we investigated the spatial relationship between pericytes (cells with cardiac repair capabilities that ensheath blood vessels) and endogenous cardiac progenitors within stem cells' niches. We explored possible changes in their co-localisation in developing human hearts from foetal to adult stage and following ischaemia. Methods: Foetal and adult human heart specimens, obtained under ethical consent (University of Edinburgh ethics committee), were used for immunohistochemistry, cell isolation, culture and differentiation. Multi-lineage differentiation in culture, by single and double staining was completed for CD 146+ foetal pericytes and c-kit+ cells. Endothelial markers (CD31) gene expression was quantified by qPCR. Results: c-kit+ cells frequency and coexpression with pericytes decrease with heart development, already evident by gestation week 19th. Pericytes and c-kit+ cells express the early cardiac transcription factors Nkx2.5 and Islet 1. Only c-kit+ cells express the stemness marker SSEA3 (24%), known to progressively decrease with cell differentiation. Endothelial differentiation assessment shows that cardiac pericytes and c-kit+ cells do not form CD31+ networks. This finding correlates with absence of staining for CD31 marker in both cultured cells' types. The cardiac marker α-actin was present in both cell populations. In healthy adult heart, pericyte markers CD146 localise within the vasculature. Following ischaemia this pericyte marker becomes also evident outside the vasculature.In healthy adult atrium, c-kit expression is low and coexpression with other markers inconspicuous. Ischaemia leads to increased c-kit expression, particularly in blood vessels <50um diameter. Furthermore, following ischaemia c-kit, endothelium and pericyte markers co-localise within the same atrial cells. Blood vessels >50μm diameter showed mostly only staining for endothelial (vWF) and pericyte (CD146) markers, with no co-expression of c-kit marker identified. Staining patterns within the ischaemic regions of the right and left atrial appendages revealed low levels of colocalisation between vWF and CD146. Acute ischaemia of the left ventricle affected the detection of cardiac stem cells markers in the area of injury, due to myocardium disruption. Conclusion: Foetal heart pericytes and c-kit+ cells express early cardiac transcription factors and show trans-differentiation potential, which decreases in healthy adult hearts. The preservation and activity of cardiac stem cells niches within the atrium vasculature appears re-activated in post-ischaemic hearts. Better understanding of cardiac c-kit+ and pericyte cells during-human embryonic development and during ischaemia may identify alternative novel therapeutic strategy against coronary artery disease. PMID: 30270958 [PubMed - in process]
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Related Articles MicroRNA-132, Delivered by Mesenchymal Stem Cell-Derived Exosomes, Promote Angiogenesis in Myocardial Infarction. Stem Cells Int. 2018;2018:3290372 Authors: Ma T, Chen Y, Chen Y, Meng Q, Sun J, Shao L, Yu Y, Huang H, Hu Y, Yang Z, Yang J, Shen Z Abstract Background: To cure ischemic diseases, angiogenesis needs to be improved by various strategies in ischemic area. Considering that microRNA-132 (miR-132) regulates endothelial cell behavior during angiogenesis and the safe and efficacious delivery of microRNAs in vivo is rarely achieved, an ideal vehicle for miR-132 delivery could bring the promise for ischemic diseases. As a natural carrier of biological molecules, exosomes are more and more developed as an ideal vehicle for miRNA transfer. Meanwhile, mesenchymal stem cells could release large amounts of exosomes. Thus, this study aimed to investigate whether MSC-derived exosomes can be used for miR-132 delivery in the treatment of myocardial ischemia. Methods: MSC-derived exosomes were electroporated with miR-132 mimics and inhibitors. After electroporation, miR-132 exosomes were labelled with DiI and added to HUVECs. Internalization of DiI-labelled exosomes was examined by fluorescent microscopy. Expression levels of miR-132 in exosomes and HUVECs were quantified by real-time PCR. The mRNA levels of miR-132 target gene RASA1 in HUVECs were quantified by real-time PCR. Luciferase reporter assay was performed to examine the targeting relationship between miR-132 and RASA1. The effects of miR-132 exosomes on the angiogenic ability of endothelial cells were evaluated by tube formation assay. Matrigel plug assay and myocardial infarction model were used to determine whether miR-132 exosomes can promote angiogenesis in vivo. Results: miR-132 mimics were effectively electroporated and highly detected in MSC-derived exosomes. The expression level of miR-132 was high in HUVECs preincubated with miR-132 mimic-electroporated exosomes and low in HUVECs preincubated with miR-132 inhibitor-electroporated exosomes. The expression level of RASA1, miR-132 target gene, was reversely correlated with miR-132 expression in HUVECs pretreated with exosomes. Luciferase reporter assay further confirmed that RASA1 was a direct target of miR-132. Exosomes loaded with miR-132, as a vehicle for miRNA transfer, significantly increased tube formation of endothelial cells. Moreover, subcutaneous injection of HUVECs pretreated with miR-132 exosomes in nude mice significantly increased their angiogenesis capacity in vivo. In addition, transplantation of miR-132 exosomes in the ischemic hearts of mice markedly enhanced the neovascularization in the peri-infarct zone and preserved heart functions. Conclusions: The findings suggest that the export of miR-132 via MSC-derived exosomes represents a novel strategy to enhance angiogenesis in ischemic diseases. PMID: 30271437 [PubMed]
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Related Articles Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat Biomed Eng. 2018 May;2(5):293-303 Authors: Liu B, Lee BW, Nakanishi K, Villasante A, Williamson R, Metz J, Kim J, Kanai M, Bi L, Brown K, Di Paolo G, Homma S, Sims PA, Topkara VK, Vunjak-Novakovic G Abstract The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been exploited for the treatment of diseases. For example, EVs secreted by stem cells injected into infarcted hearts can induce recovery through the delivery of stem-cell-specific miRNAs. However, the retention of the EVs and the therapeutic effects are short-lived. Here, we show that an engineered hydrogel patch capable of slowly releasing EVs secreted from cardiomyocytes derived from induced pluripotent stem (iPS) cells reduced arrhythmic burden, promoted ejection-fraction recovery, decreased cardiomyocyte apoptosis 24 hours after infarction, and reduced infarct size and cell hypertrophy 4 weeks post-infarction when implanted onto infarcted rat hearts. We also show that the EVs are enriched with cardiac-specific miRNAs known to modulate cardiomyocyte-specific processes. The extended delivery of EVs secreted from iPS-cell-derived cardiomyocytes into the heart may help understand heart recovery and treat heart injury. PMID: 30271672 [PubMed]
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Related Articles Primary cardiac MYC/BCL6 double hit non-Hodgkin lymphoma. J Cardiol Cases. 2018 Mar;17(3):103-106 Authors: Annibali O, Nenna A, Barbato R, Chello M, Sedati P, Bianchi A, Deda G, Avvisati G Abstract Cardiac and pericardial involvement by malignant lymphoma is a rare condition. The present case report describes a case of primary cardiac MYC/BCL6 double hit non-Hodgkin lymphoma in the pericardium, and highlights the importance of a prompt diagnosis and aggressive pharmacologic treatment of this disease. In a symptomatic patient, a minimally invasive 3 cm sub-xiphoidal incision was performed under deep sedation with spontaneous ventilation to perform a pericardial biopsy. A 5 cm × 3 cm portion of pericardium was removed from above the right ventricle, thus ameliorating the extrinsic compression on the right chambers. The patient received 6 cycles of immuno-chemotherapy (rituximab plus cyclophosphamide, vincristine, and methylprednisolone), with no complications, achieving complete remission with no symptoms. Malignancies must be excluded in every case of acute pericardial disease with imaging techniques, and lymphomas should be always considered in the differential diagnosis of cardiac tumors. Complete surgical removal of the tumor is not necessary to achieve complete remission, and minimally invasive surgical approaches are an effective tool to confirm diagnosis and allow a precise histologic characterization. <Learning objective: Primary MYC/BCL6 double hit non-Hodgkin lymphoma is a rare tumor of the pericardium, which requires prompt diagnosis and treatment. Minimally invasive surgical approaches are an effective tool to confirm diagnosis and allow a precise histologic characterization. Pericardial tumors should always be considered in the differential diagnosis of acute pericardial disease presenting with pericardial effusion. Double hit diffuse large B cell-lymphoma has a poor prognosis with standard chemotherapy and the treatment should be tailored according to the patient's comorbidities and performance status.>. PMID: 30279867 [PubMed]
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Related Articles Recent biomedical applications on stem cell therapy: A brief overview. Curr Stem Cell Res Ther. 2018 10 02;: Authors: Agrawal M, Alexander A, Khan J, Giri TK, Siddique S, Dubey SK, Ajazuddin, Patel RJ, Gupta U, Saraf S, Saraf S Abstract The unique self-renewal and differentiation ability of stem cells drag the attention of many scientists and researchers towards the clinical application of stem cells. Stem cells are basically the normal living cells of multicellular organisms with some special ability to proliferate and transform into any kind of the body cells with their characteristic feature. Talking about human stem cells, it is originated from various sources like embryonic stem cells, somatic stem cells, hematopoietic stem cells, bone marrow stem cells, neural stem cells etc. which differs in their differentiation potency. On the basis of their potency they can be applied in treatment or regeneration of different cells. Stem cell therapy having very wide range application in treatment of various diseases. In this review article we have summarized the application of stem cell as regenerative medicine and treatment of chronic disorders. PMID: 30280676 [PubMed - as supplied by publisher]
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Related Articles Genetic and Tissue Engineering Approaches to Modeling the Mechanics of Human Heart Failure for Drug Discovery. Front Cardiovasc Med. 2018;5:120 Authors: Greenberg MJ, Daily NJ, Wang A, Conway MK, Wakatsuki T Abstract Heart failure is the leading cause of death in the western world and as such, there is a great need for new therapies. Heart failure has a variable presentation in patients and a complex etiology; however, it is fundamentally a condition that affects the mechanics of cardiac contraction, preventing the heart from generating sufficient cardiac output under normal operating pressures. One of the major issues hindering the development of new therapies has been difficulties in developing appropriate in vitro model systems of human heart failure that recapitulate the essential changes in cardiac mechanics seen in the disease. Recent advances in stem cell technologies, genetic engineering, and tissue engineering have the potential to revolutionize our ability to model and study heart failure in vitro. Here, we review how these technologies are being applied to develop personalized models of heart failure and discover novel therapeutics. PMID: 30283789 [PubMed]
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Related Articles Development of the Myocardial Interstitium. Anat Rec (Hoboken). 2018 Oct 05;: Authors: Pogontke C, Guadix JA, Ruiz-Villalba A, Pérez-Pomares JM Abstract The space between cardiac myocytes is commonly referred-to as the cardiac interstitium (CI). The CI is a unique, complex and dynamic microenvironment in which multiple cell types, extracellular matrix molecules, and instructive signals interact to crucially support heart homeostasis and promote cardiac responses to normal and pathologic stimuli. Despite the biomedical and clinical relevance of the CI, its detailed cellular structure remains to be elucidated. In this review, we will dissect the organization of the cardiac interstitium by following its changing cellular and molecular composition from embryonic developmental stages to adulthood, providing a systematic analysis of the biological components of the CI. The main goal of this review is to contribute to our understanding of the CI roles in health and disease. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. PMID: 30288955 [PubMed - as supplied by publisher]
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Related Articles Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia. Leukemia. 2018 Oct 05;: Authors: Yan B, Chen Q, Shimada K, Tang M, Li H, Gurumurthy A, Khoury JD, Xu B, Huang S, Qiu Y Abstract Chemoresistance may be due to the survival of leukemia stem cells (LSCs) that are quiescent and not responsive to chemotherapy or lie on the intrinsic or acquired resistance of the specific pool of AML cells. Here, we found, among well-established LSC markers, only CD123 and CD47 are correlated with AML cell chemosensitivities across cell lines and patient samples. Further study reveals that percentages of CD123+CD47+ cells significantly increased in chemoresistant lines compared to parental cell lines. However, stemness signature genes are not significantly increased in resistant cells. Instead, gene changes are enriched in cell cycle and cell survival pathways. This suggests CD123 may serve as a biomarker for chemoresistance, but not stemness of AML cells. We further investigated the role of epigenetic factors in regulating the survival of chemoresistant leukemia cells. Epigenetic drugs, especially histone deacetylase inhibitors (HDACis), effectively induced apoptosis of chemoresistant cells. Furthermore, HDACi Romidepsin largely reversed gene expression profile of resistant cells and efficiently targeted and removed chemoresistant leukemia blasts in xenograft AML mouse model. More interestingly, Romidepsin preferentially targets CD123+ cells, while chemotherapy drug Ara-C mainly targeted fast-growing, CD123- cells. Therefore, Romidepsin alone or in combination with Ara-C may be a potential treatment strategy for chemoresistant patients. PMID: 30291336 [PubMed - as supplied by publisher]
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Related Articles Over-expression of PD-1 Does Not Predict Leukemic Relapse after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2018 Oct 04;: Authors: Jain P, Tian X, Cordes S, Chen J, Cantilena CR, Bradley C, Panjwani R, Chinian F, Keyvanfar K, Battiwalla M, Muranski P, Barrett AJ, Ito S Abstract Blockade of the T-cell exhaustion marker PD-1 to re-energize the immune response is emerging as a promising cancer treatment. Relapse of hematologic malignancy after allogeneic stem cell transplantation limits the success of this approach, and PD-1 blockade may hold therapeutic promise. However, PD-1 expression and its relationship with post-transplant relapse is poorly described. Because the donor immunity is activated by alloresponses, PD-1 expression may differ from nontransplanted individuals, and PD-1 blockade could risk graft-versus-host disease. Here we analyzed T-cell exhaustion marker kinetics and their relationship with leukemia relapse in 85 patients undergoing myeloablative T-cell-depleted HLA-matched stem cell transplantation. At a median follow-up of 3.5 years, 35 (44%) patients relapsed. PD-1 expression in CD4 and CD8 T cells was comparably elevated in relapsed and nonrelapsed cohorts. Helios+ regulatory T cells and CD8 effector memory cells at day 30 emerged as independent predictors of relapse. Although leukemia antigen-specific T cells did not overexpress PD-1, single-cell analysis revealed LAG3 and TIM3 overexpression at relapse. These findings indicate that PD-1 is an unreliable marker for leukemia-specific T-cell exhaustion in relapsing patients but implies other exhaustion markers and suppressor cells as relapse biomarkers. PMID: 30292745 [PubMed - as supplied by publisher]
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Related Articles Multistate modeling and simulation of patient trajectories after allogeneic hematopoietic stem cell transplantation to inform drug development. Biom J. 2018 Sep 17;: Authors: James DA, Ng J, Wei J, Vandemeulebroecke M Abstract We present a case study for developing clinical trial scenarios in a complex progressive disease with multiple events of interest. The idea is to first capture the course of the disease in a multistate Markov model, and then to simulate clinical trials from this model, including a variety of hypothesized drug effects. This case study focuses on the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). The patient trajectory after HSCT is characterized by a complex interplay of various events of interest, and there is no established best method of measuring and/or analyzing treatment benefits. We characterized patient trajectories by means of multistate models that we fitted to a subset of the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Events of interest included acute GvHD of grade III or IV, severe chronic GvHD, relapse of the underlying disease, and death. The transition probability matrix was estimated using the Aalen-Johansen estimator, and patient characteristics were identified that were associated with different transition rates. In a second step, clinical trial scenarios were simulated from the model assuming various drug effects on the background transition rates, and the operating characteristics of different endpoints and analysis strategies were compared in these scenarios. This helped devise a drug development strategy in GvHD prevention after allogeneic HSCT. More generally, multistate models provide a rich framework for exploring complex progressive diseases, and the availability of a corresponding simulation machinery provides great flexibility for clinical trial planning. PMID: 30295953 [PubMed - as supplied by publisher]
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Related Articles Spatiotemporal mosaic self-patterning of pluripotent stem cells using CRISPR interference. Elife. 2018 10 09;7: Authors: Libby AR, Joy DA, So PL, Mandegar MA, Muncie JM, Mendoza-Camacho FN, Weaver VM, Conklin BR, McDevitt TC Abstract Morphogenesis involves interactions of asymmetric cell populations to form complex multicellular patterns and structures comprised of distinct cell types. However, current methods to model morphogenic events lack control over cell-type co-emergence and offer little capability to selectively perturb specific cell subpopulations. Our in vitro system interrogates cell-cell interactions and multicellular organization within human induced pluripotent stem cell (hiPSC) colonies. We examined effects of induced mosaic knockdown of molecular regulators of cortical tension (ROCK1) and cell-cell adhesion (CDH1) with CRISPR interference. Mosaic knockdown of ROCK1 or CDH1 resulted in differential patterning within hiPSC colonies due to cellular self-organization, while retaining an epithelial pluripotent phenotype. Knockdown induction stimulates a transient wave of differential gene expression within the mixed populations that stabilized in coordination with observed self-organization. Mosaic patterning enables genetic interrogation of emergent multicellular properties, which can facilitate better understanding of the molecular pathways that regulate symmetry-breaking during morphogenesis. PMID: 30298816 [PubMed - in process]
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Related Articles Human Neonatal Thymus Mesenchymal Stem Cells Promote Neovascularization and Cardiac Regeneration. Stem Cells Int. 2018;2018:8503468 Authors: Wang S, Huang S, Gong L, Yuan Z, Wong J, Lee J, Si MS Abstract Newborns with critical congenital heart disease are at significant risk of developing heart failure later in life. Because treatment options for end-stage heart disease in children are limited, regenerative therapies for these patients would be of significant benefit. During neonatal cardiac surgery, a portion of the thymus is removed and discarded. This discarded thymus tissue is a good source of MSCs that we have previously shown to be proangiogenic and to promote cardiac function in an in vitro model of heart tissue. The purpose of this study was to further evaluate the cardiac regenerative and protective properties of neonatal thymus (nt) MSCs. We found that ntMSCs expressed and secreted the proangiogenic and cardiac regenerative morphogen sonic hedgehog (Shh) in vitro more than patient-matched bone-derived MSCs. We also found that organoid culture of ntMSCs stimulated Shh expression. We then determined that ntMSCs were cytoprotective of neonatal rat cardiomyocytes exposed to H2O2. Finally, in a rat left coronary ligation model, we found that scaffoldless cell sheet made of ntMSCs applied to the LV epicardium immediately after left coronary ligation improved LV function, increased vascular density, decreased scar size, and decreased cardiomyocyte death four weeks after infarction. We conclude that ntMSCs have cardiac regenerative properties and warrant further consideration as a cell therapy for congenital heart disease patients with heart failure. PMID: 30305821 [PubMed]
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Related Articles Clinical Proteomics for Post-Hematopoeitic Stem Cell Transplantation Outcomes. Proteomics Clin Appl. 2018 Oct 11;:e1800145 Authors: Paczesny S, Metzger J Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective form of tumor immunotherapy available to date. However, while HSCT can induce beneficial graft-versus-leukemia (GVL) effect, the adverse effect of graft-versus-host disease (GVHD), which is closely linked to GVL, is the major source of morbidity and mortality following HSCT. Until recently, available diagnostic and staging tools frequently fail to identify those at higher risk of disease progression or death. Furthermore, there are shortcomings in the prediction of the need for therapeutic interventions or the response rates to different forms of therapy. The past decade has been characterized by an explosive evolution of proteomics technologies, largely due to important advances in high-throughput MS instruments and bioinformatics. Building on these opportunities, blood biomarkers have been identified and validated both as promising diagnostic tools, prognostic tools that risk-stratify patients before future occurrence of GVHD and as predictive tools for responsiveness to GVHD therapy and non-relapse mortality. These biomarkers might facilitate timely and selective therapeutic intervention. This review summarizes current information on clinical proteomics for GVHD as well as other complications following HSCT. Finally, it proposes future directions for the translation of clinical proteomics to discovery of new potential therapeutic targets to the development of drugs. PMID: 30307119 [PubMed - as supplied by publisher]
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Related Articles α-Lipoic acid and amlodipine/perindopril combination potentiate the therapeutic effect of mesenchymal stem cells on isoproterenol induced cardiac injury in rats. Biochimie. 2018 Oct 08;156:59-68 Authors: Abd El-Fattah AI, Zaghloul MS, Eltablawy NA, Rashed LA Abstract Cardiac injury is a dangerous disease and become a greater issue in the forthcoming decades. The ultimate goal is to prevent the progression of heart failure and apoptotic processes. Cardiac tissue may regenerate itself but to certain extent depending on the number of resident stem cells that is limited. Thus, research had been focused on bone marrow derived stem cells (BM-MSCs) as a promising therapy in different types of tissues, including the heart. This study is designed not only to assess the therapeutic effect of BM-MSCs but also to improve their therapeutic effect in combination with antioxidant α-lipoic acid (ALA) and antihypertensive therapeutic drug form (AP) against isoproterenol-induced cardiac injury and compared with that of BM-MSCs alone. Cardiac injury was induced in 70 male rats by Isoproterenol (ISO was injected s.c. for four consecutive days). Experimental animals were divided into six ISO-treated groups beside a control non treated one. The six ISO-treated groups were divided into: ISO group, ISO+BM-MSCs group, ISO+ALA group, ISO+AP group, ISO+ALA+AP group and ISO+ALA+AP+BM-MSCs group, the last five groups were treated with the examined materials after one week of ISO injection. Isoproterenol significantly increased serum CK-MB, LDH activities, Troponin1 and TNF-α. Oxidative stress is evidenced by the increased MDA, NO and Caspase-3 activity associated with significant reduction of GSH content and SOD activity in cardiac tissue. Furthermore, mRNA expression of NFκB and iNOS were significantly up regulated and eNOS mRNA expression was down regulated. Administration of BM-MSCs, ALA and AP alone significantly mitigated the induced cardiac injury. Concomitant administration of ALA and AP after BM-MSCs induced a more pronounced improving effect on cardiac functions. In conclusion, the concomitant administration of ALA and AP after BM-MSCs infusion increases the cellular antioxidant levels of cardiac tissue that improves the repairing function of BM-MSCs. PMID: 30308238 [PubMed - as supplied by publisher]
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Related Articles Generation of a Urine-Derived Ips Cell Line from a Patient with a Ventricular Septal Defect and Heart Failure and the Robust Differentiation of These Cells to Cardiomyocytes via Small Molecules. Cell Physiol Biochem. 2018;50(2):538-551 Authors: Cao Y, Xu J, Wen J, Ma X, Liu F, Li Y, Chen W, Sun L, Wu Y, Li S, Li J, Huang G Abstract BACKGROUND/AIMS: Ventricular septal defects (VSDs) are one of the most common types of congenital heart malformations. Volume overload resulting from large VSDs can lead to heart failure (HF) and constitutes a major cause of pediatric HF with a series of often-fatal consequences. The etiology of VSD with HF is complex, and increasing evidence points toward a genetic basis. Indeed, we identified an L2483R mutation in the ryanodine receptor type 2 (RyR2) in a 2-month-old male patient with VSD with HF. METHODS: We generated integration-free induced pluripotent stem cells from urine samples (UiPSCs) of this patient using Sendai virus containing the Yamanaka factors and characterized these cells based on alkaline phosphatase activity, pluripotency marker expression, and teratoma formation. Then, we induced the derived UiPSCs to rapidly and efficiently differentiate into functional cardiomyocytes through temporal modulation of canonical Wnt signaling with small molecules. Real-time PCR and immunofluorescence were used to verify the expression of myocardium-specific markers in the differentiated cardiomyocytes. The ultrastructure of the derived myocardial cells was further analyzed by using transmission electron microscopy. RESULTS: The established UiPSC lines were positive for alkaline phosphatase activity, retained the RyR2 mutation, expressed pluripotency markers, and displayed differentiation potential to three germ layers in vivo. The UiPSC-derived cells showed hallmarks of cardiomyocytes, including spontaneous contraction and strong expression of cardiac-specific proteins and genes. However, compared with cardiomyocytes derived from H9 cells, they had a higher level of autophagy, implying that autophagy may play an important role in the development of VSD with HF. CONCLUSION: The protocol described here yields abundant myocardial cells and provides a solid platform for further investigation of the pathogenesis, pharmacotherapy, and gene therapy of VSD with HF. PMID: 30308486 [PubMed - indexed for MEDLINE]
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Related Articles The use of stem cells in ischemic heart disease treatment. Kardiochir Torakochirurgia Pol. 2018 Sep;15(3):196-199 Authors: Litwinowicz R, Kapelak B, Sadowski J, Kędziora A, Bartus K Abstract Ischemic heart disease is a major cause of death and disabilities worldwide. Unfortunately, not all patients are suitable for direct revascularization. Cell-based therapies may be alternative options because of their potential to promote neovascularisation and endothelial repair, improving myocardial perfusion. The success of cell-based therapies depends on the type of implanted stem cells, delivery method and underlying disease. Several different cell populations including bone marrow-derived mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), CD34+, CD133+, endothelial progenitor cells, adipose-derived mesenchymal stromal cells (ASCs) and stem cells from placenta and umbilical cord have been investigated. Presently, no consensus exists about the best cell type for clinical regenerative therapy. Because the system of coronary arteries in the ischemic area is poor and most of the coronary artery is significantly narrowed or closed, direct implantation of stem cells in the ischemic area of the heart muscle appears an attractive method. PMID: 30310400 [PubMed]
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Related Articles New Advances in the Management of Refractory Angina Pectoris. Eur Cardiol. 2018 Aug;13(1):70-79 Authors: Cheng K, de Silva R Abstract Refractory angina is a significant clinical problem and its successful management is often extremely challenging. Defined as chronic angina-type chest pain in the presence of myocardial ischaemia that persists despite optimal medical, interventional and surgical treatment, current therapies are limited and new approaches to treatment are needed. With an ageing population and increased survival from coronary artery disease, clinicians will increasingly encounter this complex condition in routine clinical practice. Novel therapies to target myocardial ischaemia in patients with refractory angina are at the forefront of research and in this review we discuss those in clinical translation and assess the evidence behind their efficacy. PMID: 30310476 [PubMed]
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Related Articles Pathobiology, pathology and genetics of pulmonary hypertension: Update from the Cologne Consensus Conference 2018. Int J Cardiol. 2018 Sep 20;: Authors: Olschewski A, Berghausen EM, Eichstaedt CA, Fleischmann BK, Grünig E, Grünig G, Hansmann G, Harbaum L, Hennigs JK, Jonigk D, Kuebler WM, Kwapiszewska G, Pullamsetti SS, Stacher E, Weissmann N, Wenzel D, Schermuly RT Abstract The European guidelines, which focus on clinical aspects of pulmonary hypertension (PH), provide only minimal information about the pathophysiological concepts of PH. Here, we review this topic in greater detail, focusing on specific aspects in the pathobiology, pathology and genetics, which include mechanisms of vascular inflammation, the role of transcription factors, ion channels/ion channel diseases, hypoxic pulmonary vasoconstriction, genetics/epigenetics, metabolic dysfunction, and the potential future role of histopathology of PH in the modern era of PH therapy. In addition to new insights in the pathobiology of this disease, this working group of the Cologne Consensus Conference also highlights novel concepts and potential new therapeutic targets to further improve the treatment options in PAH. PMID: 30314839 [PubMed - as supplied by publisher]
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Related Articles Interleukin-18 plays a dispensable role in murine and likely also human bone marrow failure. Exp Hematol. 2018 Oct 12;: Authors: Wu Z, Giudice V, Chen J, Sun W, Lin Z, Keyvanfar K, Talasani N, Kajigaya S, Feng X, Young NS Abstract Interleukin-18 (IL-18), also known as interferon-gamma (IFN-γ)-inducing factor, is involved in Th1 responses and regulation of immunity. Accumulating evidence implicates IL-18 in autoimmune diseases, but little is known of its role in acquired aplastic anemia (AA), the immune-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). IL-18 protein levels were significantly elevated in sera of severe AA (SAA) patients, including both responders and nonresponders assayed before treatment, and decreased after treatment. IL-18 receptor (IL-18R) was expressed on HSPCs. Co-culture of human BM CD34+ cells from healthy donors with IL-18 upregulated genes in the helper T-cell and Notch signaling pathways and downregulated genes in the cell cycle regulation, telomerase, and IL-6 signaling pathways. Plasma IL-18 levels were also elevated in murine models of immune-mediated BM failure. However, deletion of IL-18 in donor lymph node cells or deletions of either IL-18 or IL-18R in recipients did not attenuate elevations of circulating IFN-γ, tumor necrosis factor-alpha, or IL-6, nor did they alleviate BM failure. In summary, our findings suggest that, although increased circulating IL-18 is a feature of SAA, it may reflect an aberrant immune response but be dispensable to the pathogenesis of AA. PMID: 30316805 [PubMed - as supplied by publisher]
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Related Articles Fluorescence properties of curcumin-loaded nanoparticles for cell tracking. Int J Nanomedicine. 2018;13:5823-5836 Authors: Mogharbel BF, Francisco JC, Irioda AC, Dziedzic DSM, Ferreira PE, de Souza D, de Souza CMCO, Neto NB, Guarita-Souza LC, Franco CRC, Nakamura CV, Kaplum V, Mazzarino L, Lemos-Senna E, Borsali R, Soto PA, Setton-Avruj P, Abdelwahid E, de Carvalho KAT Abstract Background: Posttransplant cell tracking, via stem cell labeling, is a crucial strategy for monitoring and maximizing benefits of cell-based therapies. The structures and functionalities of polysaccharides, proteins, and lipids allow their utilization in nanotechnology systems. Materials and methods: In the present study, we analyzed the potential benefit of curcumin-loaded nanoparticles (NPC) using Vero cells (in vitro) and NPC-labeled adipose-derived mesenchymal stem cells (NPC-ADMSCs) (in vivo) in myocardial infarction and sciatic nerve crush preclinical models. Thereafter, transplantation, histological examination, real time imaging, and assessment of tissue regeneration were done. Results: Transplanted NPC-ADMSCs were clearly identified and revealed potential benefit when used in cell tracking. Conclusion: This approach may have broad applications in modeling labeled transplanted cells and in developing improved stem cell therapeutic strategies. PMID: 30319253 [PubMed - indexed for MEDLINE]
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Related Articles Stem Cell Homing: a Potential Therapeutic Strategy Unproven for Treatment of Myocardial Injury. J Cardiovasc Transl Res. 2018 Oct;11(5):403-411 Authors: Tao Z, Tan S, Chen W, Chen X Abstract Despite advances in the prevention and therapeutic modalities of ischemic heart disease, morbidity and mortality post-infarction heart failure remain big challenges in modern society. Stem cell therapy is emerging as a promising therapeutic strategy. Stem cell homing, the ability of stem cells to find their destination, is receiving more attention. Identification of specific cues and understanding the signaling pathways that direct stem cells to targeted destination will improve stem cell homing efficiency. This review discusses the cellular and molecular mechanism of stem cell homing at length in the light of literature and analyzes the problem and considerations of this approach as a treatment strategy for the treatment of ischemic heart disease clinically. PMID: 30324254 [PubMed - in process]
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Related Articles Cell-Based Therapies for Cardiac Regeneration: A Comprehensive Review of Past and Ongoing Strategies. Int J Mol Sci. 2018 Oct 16;19(10): Authors: Ghiroldi A, Piccoli M, Cirillo F, Monasky MM, Ciconte G, Pappone C, Anastasia L Abstract Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients' clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach. PMID: 30332812 [PubMed - in process]
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Related Articles Cardiac Regeneration with Human Pluripotent Stem Cell-Derived Cardiomyocytes. Korean Circ J. 2018 Nov;48(11):974-988 Authors: Park M, Yoon YS Abstract Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which are collectively called pluripotent stem cells (PSCs), have emerged as a promising source for regenerative medicine. Particularly, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have shown robust potential for regenerating injured heart. Over the past two decades, protocols to differentiate hPSCs into CMs at high efficiency have been developed, opening the door for clinical application. Studies further demonstrated therapeutic effects of hPSC-CMs in small and large animal models and the underlying mechanisms of cardiac repair. However, gaps remain in explanations of the therapeutic effects of engrafted hPSC-CMs. In addition, bioengineering technologies improved survival and therapeutic effects of hPSC-CMs in vivo. While most of the original concerns associated with the use of hPSCs have been addressed, several issues remain to be resolved such as immaturity of transplanted cells, lack of electrical integration leading to arrhythmogenic risk, and tumorigenicity. Cell therapy with hPSC-CMs has shown great potential for biological therapy of injured heart; however, more studies are needed to ensure the therapeutic effects, underlying mechanisms, and safety, before this technology can be applied clinically. PMID: 30334384 [PubMed]
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Related Articles Human iPS cell-engineered three-dimensional cardiac tissues perfused by capillary networks between host and graft. Inflamm Regen. 2018;38:26 Authors: Masumoto H, Yamashita JK Abstract Stem cell-based cardiac regenerative therapy is expected to be a promising strategy for the treatment of severe heart diseases. Pluripotent stem cells enabled us to reconstruct regenerated myocardium in injured hearts as an engineered tissue aiming for cardiac regeneration. To establish a long-term survival of transplanted three-dimensional (3D) engineered heart tissues in vivo, it is indispensable to induce microcapillaries into the engineered tissues after transplantation. Using temperature-responsive culture surface, we have developed pluripotent stem cell-derived cardiac tissue sheets including multiple cardiac cell lineages. The application of gelatin hydrogel microsphere between the cell sheet stacks enabled us to generate thick stacked cell sheets with functional vascular network in vivo. Another technology to generate 3D engineered cardiac tissues using cardiac cells and biomaterials also validated successful induction of vascular network originated from both host and graft-derived vascular cells. PMID: 30338009 [PubMed]
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Related Articles Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution. Biol Blood Marrow Transplant. 2018 Oct 18;: Authors: Melendez-Munoz R, Marchalik R, Jerussi T, Dimitrova D, Nussenblatt V, Beri A, Rai K, Wilder JS, Barrett AJ, Battiwalla M, Childs RW, Fitzhugh CD, Fowler DH, Fry TJ, Gress RE, Hsieh MM, Ito S, Kang EM, Pavletic SZ, Shah NN, Tisdale JF, Gea-Banacloche J, Kanakry CG, Kanakry JA Abstract Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36 days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21 days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis. PMID: 30342913 [PubMed - as supplied by publisher]
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Related Articles Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models. Stem Cell Rev. 2018 Oct 20;: Authors: Granéli C, Hicks R, Brolén G, Synnergren J, Sartipy P Abstract The global burden of diabetes has drastically increased over the past decades and in 2017 approximately 4 million deaths were caused by diabetes and cardiovascular complications. Diabetic cardiomyopathy is a common complication of diabetes with early manifestations of diastolic dysfunction and left ventricular hypertrophy with subsequent progression to systolic dysfunction and ultimately heart failure. An in vitro model accurately recapitulating key processes of diabetic cardiomyopathy would provide a useful tool for investigations of underlying disease mechanisms to further our understanding of the disease and thereby potentially advance treatment strategies for patients. With their proliferative capacity and differentiation potential, human induced pluripotent stem cells (iPSCs) represent an appealing cell source for such a model system and cardiomyocytes derived from induced pluripotent stem cells have been used to establish other cardiovascular related disease models. Here we review recently made advances and discuss challenges still to be overcome with regard to diabetic cardiomyopathy models, with a special focus on iPSC-based systems. Recent publications as well as preliminary data presented here demonstrate the feasibility of generating cardiomyocytes with a diabetic phenotype, displaying insulin resistance, impaired calcium handling and hypertrophy. However, capturing the full metabolic- and functional phenotype of the diabetic cardiomyocyte remains to be accomplished. PMID: 30343468 [PubMed - as supplied by publisher]
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Related Articles Endothelial stem cells attenuate cardiac apoptosis via downregulating cardiac microRNA-146a in a rat model of coronary heart disease. Exp Ther Med. 2018 Nov;16(5):4246-4252 Authors: Fang Y, Chen S, Liu Z, Ai W, He X, Wang L, Xie P, Jiang B, Fang H Abstract Coronary artery disease (CAD) is one of the main causes of hospitalization worldwide and has high morbidity. It has previously been demonstrated that stem cells serve an important role in improving myocardial function. MicroRNA (miRNA)-146a downregulation has been reported to inhibit vascular smooth muscle cell apoptosis in a rat model of coronary heart disease. The aim of the present study was to investigate the mechanisms underlying the effects of endothelial stem cell (ESC)-derived paracrine factors and cardiac miRNAs in CAD. Acute myocardial infarction was induced in 20 rats. Autologous ESCs (n=10; experimental group) or PBS (n=10; control group) were injected in the border zone. Reverse transcription-quantitative polymerase chain reaction, ELISA and immunohistochemistry assays were performed to analyze the therapeutic effects of ESCs in rats with coronary heart disease rats. Serum interleukin (IL)-1, IL-17 and tumor necrosis factor-α were reduced in the experimental group compared with control rats, as was the number of circulating proatherogenic cells. The results demonstrated that ESC transplantation markedly downregulated miRNA-146a expression and decreased apoptosis in the myocardium compared with the control group. Rats in the experimental group also had higher levels of vascular endothelial growth factor compared with the control group. In addition, it was demonstrated that miRNA-146 knockdown reduced cardiac apoptosis and increased VEGF expression. Furthermore, the infarct area in the border zone or rats with CAD was reduced in the experimental group compared with the control group. In conclusion, these results suggest that ESC transplantation may improve cardiac function via downregulating miR-146a, which may be have potential as a treatment for CAD. PMID: 30344699 [PubMed]
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Related Articles Allogeneic Mesenchymal Stem Cells and Biomaterials: The Perfect Match for Cardiac Repair? Int J Mol Sci. 2018 Oct 19;19(10): Authors: Perez-Estenaga I, Prosper F, Pelacho B Abstract Coronary heart disease is the leading cause of death worldwide with huge socio-economic consequences. Cell therapy, and particularly mesenchymal stem cells (MSC), are considered a promising option to treat this disorder, due to their robust trophic and immunomodulatory properties. However, limitations such as their low rate of engraftment and poor survival after administration into the heart have precluded their large-scale clinical use. Nevertheless, the combination of MSC with polymer-made scaffolds or hydrogels has proven to enhance their retention and, therefore, their efficacy. Additionally, their allogeneic use could permit the creation of ready-to-use cell patches able to improve their feasibility and promote their application in clinical settings. In this review, the experimental and clinical results derived from the use of MSC in cardiac pathology, as well as advances in the bioengineering field to improve the potential of therapeutic cells, are extensively discussed. Additionally, the current understanding of the heart response to the allogeneic MSC transplants is addressed. PMID: 30347686 [PubMed - in process]
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Related Articles Trypanosoma cruzi Neurotrophic Factor Facilitates Cardiac Repair in a Mouse Model of Chronic Chagas Disease. J Pharmacol Exp Ther. 2018 Oct 22;: Authors: Ledoux T, Aridgides D, Salvador R, Ngwenyama N, Panagiotidou S, Alcaide P, Blanton R, Perrin MA Abstract Most patients acutely infected with Trypanosoma cruzi undergo short-term structural and functional cardiac alterations that heal without sequelae. By contrast, in patients whose disease progresses to chronic infection, irreversible degenerative chronic Chagas cardiomyopathy (CCC) may develop. To account for the contrast between cardiac regeneration in high-parasitism acute infection and progressive cardiomyopathy in low-parasitism CCC, we hypothesized that T. cruzi expresses repair factors that directly facilitate cardiac regeneration. We investigated the T. cruzi Parasite-Derived Neurotrophic Factor (PDNF), known to trigger survival of cardiac myocytes and fibroblasts and upregulate chemokine CCL2, which promotes migration of regenerative cardiac progenitor cells (CPCs), as one such repair factor. We tested whether T. cruzi PDNF promotes cardiac repair using in vivo and in vitro models of Chagas disease. qPCR and flow cytometry of heart tissue revealed that Sca-1+ CPCs expand in acute infection in parallel to parasitism. Recombinant PDNF induced survival and expansion of ex vivo CPCs, and intravenous administration of PDNF into naive mice upregulated mRNA of cardiac stem cell marker Sca-1. Furthermore, in CCC mice, a three-week intravenous administration of PDNF protocol induced CPC expansion and reversed left ventricular T cell accumulation and cardiac remodeling including fibrosis. Compared to CCC vehicle-treated mice, which developed severe atrioventricular block, PDNF-treated mice exhibited reduced frequency and severity of conduction abnormalities. Our findings are in support of the novel concept that T. cruzi uses PDNF to promote mutually beneficial cardiac repair in Chagas disease. This could indicate a possible path to prevention or treatment of CCC. PMID: 30348750 [PubMed - as supplied by publisher]
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Related Articles Silencing the CSF-1 Axis Using Nanoparticle Encapsulated siRNA Mitigates Viral and Autoimmune Myocarditis. Front Immunol. 2018;9:2303 Authors: Meyer IS, Goetzke CC, Kespohl M, Sauter M, Heuser A, Eckstein V, Vornlocher HP, Anderson DG, Haas J, Meder B, Katus HA, Klingel K, Beling A, Leuschner F Abstract Myocarditis is an inflammatory disease of the heart muscle most commonly caused by viral infection and often maintained by autoimmunity. Virus-induced tissue damage triggers chemokine production and, subsequently, immune cell infiltration with pro-inflammatory and pro-fibrotic cytokine production follows. In patients, the overall inflammatory burden determines the disease outcome. Following the aim to define specific molecules that drive both immunopathology and/or autoimmunity in inflammatory heart disease, here we report on increased expression of colony stimulating factor 1 (CSF-1) in patients with myocarditis. CSF-1 controls monocytes originating from hematopoietic stem cells and subsequent progenitor stages. Both, monocytes and macrophages are centrally involved in mediating tissue damage and fibrotic scarring in the heart. CSF-1 influences monocytes via engagement of CSF-1 receptor, and it is also produced by cells of the mononuclear phagocyte system themselves. Based on this, we sought to modulate the virus-triggered inflammatory response in an experimental model of Coxsackievirus B3-induced myocarditis by silencing the CSF-1 axis in myeloid cells using nanoparticle-encapsulated siRNA. siCSF-1 inverted virus-mediated immunopathology as reflected by lower troponin T levels, a reduction of accumulating myeloid cells in heart tissue and improved cardiac function. Importantly, pathogen control was maintained and the virus was efficiently cleared from heart tissue. Since viral heart disease triggers heart-directed autoimmunity, in a second approach we investigated the influence of CSF-1 upon manifestation of heart tissue inflammation during experimental autoimmune myocarditis (EAM). EAM was induced in Balb/c mice by immunization with a myocarditogenic myosin-heavy chain-derived peptide dissolved in complete Freund's adjuvant. siCSF-1 treatment initiated upon established disease inhibited monocyte infiltration into heart tissue and this suppressed cardiac injury as reflected by diminished cardiac fibrosis and improved cardiac function at later states. Mechanistically, we found that suppression of CSF-1 production arrested both differentiation and maturation of monocytes and their precursors in the bone marrow. In conclusion, during viral and autoimmune myocarditis silencing of the myeloid CSF-1 axis by nanoparticle-encapsulated siRNA is beneficial for preventing inflammatory tissue damage in the heart and preserving cardiac function without compromising innate immunity's critical defense mechanisms. PMID: 30349538 [PubMed - in process]
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Related Articles A Path Forward for Regenerative Medicine. Circ Res. 2018 Aug 03;123(4):495-505 Authors: Fanaroff AC, Morrow V, Krucoff MW, Seltzer JH, Perin EC, Taylor DA, Miller LW, Zeiher AM, Fernández-Avilés F, Losordo DW, Henry TD, Povsic TJ Abstract Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac Safety Research Consortium sponsored a session during the Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine in September 2017. This session convened leaders in cardiovascular regenerative medicine, including participants from academia, the pharmaceutical industry, the US Food and Drug Administration, and the Cardiac Safety Research Consortium, with particular focus on treatments closest to regulatory approval. A goal of the session was to identify barriers to regulatory approval and potential pathways to overcome them. Barriers identified include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical end points required for regulatory decisions. Strategies to overcome these barriers include precompetitive development of a cell therapy registry network to enable dual-purposing of clinical data as part of pragmatic clinical trial design, development of standardized terminology for product activity and end points to facilitate this registry, use of innovative statistical methods and quality of life or functional end points to supplement outcomes such as death or heart failure hospitalization and reduce sample size, involvement of patients in determining the research agenda, and use of the Food and Drug Administration's new Regenerative Medicine Advanced Therapy designation to facilitate early discussion with regulatory authorities when planning development pathways. PMID: 30355250 [PubMed - in process]
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Related Articles Highly Efficient CRISPR-Cas9-Mediated Genome Editing in Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol. 2018 Oct 24;:e64 Authors: Maguire JA, Cardenas-Diaz FL, Gadue P, French DL Abstract Human PSCs offer tremendous potential for both basic biology and cell-based therapies for a wide variety of diseases. The ability to manipulate the genome of these cells using the CRISPR-Cas9 technology has expanded this potential by providing a valuable tool for engineering or correcting disease-associated mutations. Because of the high efficiency with which CRISPR-Cas9 creates targeted double-strand breaks, a major challenge has been the introduction of precise genetic modifications on one allele, without indel formation on the non-targeted allele. To overcome this obstacle, we describe the use of two oligonucleotides, one expressing the sequence change, with the other maintaining the normal sequence. In addition, we have streamlined both the transfection and screening methodology to make this protocol efficient with small numbers of cells and to limit the amount of labor-intensive clone passaging. This protocol provides a streamlined and technically simple approach for generating valuable tools to model human disease in stem cells. © 2018 by John Wiley & Sons, Inc. PMID: 30358158 [PubMed - as supplied by publisher]
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Related Articles Sphingosine 1-phosphate promotes mesenchymal stem cell-mediated cardioprotection against myocardial infarction via ERK1/2-MMP-9 and Akt signaling axis. Life Sci. 2018 Dec 15;215:31-42 Authors: Chen R, Cai X, Liu J, Bai B, Li X Abstract AIMS: The sphingolipid metabolite sphingosine 1‑phosphate (S1P) has emerged as a potential cardioprotective molecule against ischemic heart disease. Moreover, S1P triggers mobilization and homing of bone marrow-derived stem/progenitor cells into the damaged heart. However, it remains elusive whether S1P promotes mesenchymal stem cells (MSCs)-mediated cardioprotection against ischemic heart diseases. MAIN METHODS: Adipose tissue-derived MSCs (AT-MSCs) were obtained from GFP transgenic mice or C57BL/6J. Myocardial infarction (MI) was induced in C57BL/6J mice by ligation of the left anterior descending coronary artery (LAD). Subsequently, S1P-treated AT-MSCs or vehicle-treated AT-MSCs were intravenously administered for 24 h after induction of MI or sham procedure. KEY FINDINGS: Pre-conditioning with S1P significantly enhanced the migratory and anti-apoptotic efficacies of AT-MSCs. In MI-induced mice, intravenous administration of S1P-treated AT-MSCs significantly augmented their homing and engraftment in ischemic area. Besides, AT-MSCs with S1P pre-treatment exhibited enhanced potencies to inhibit cardiomyocyte apoptosis and fibrosis, and stimulate angiogenesis and preserve cardiac function. Mechanistic studies revealed that S1P promoted AT-MSCs migration through activation of ERK1/2-MMP-9, and protected AT-MSCs against apoptosis via Akt activation. Further, S1P activated the ERK1/2 and Akt via S1P receptor 2 (S1PR2), but not through S1PR1. S1PR2 knockdown by siRNA, however, significantly attenuated S1P-mediated AT-MSCs migration and anti-apoptosis. SIGNIFICANCE: The findings of the present study revealed the protective efficacies of S1P pretreatment on the survival/retention and cardioprotection of engrafted MSCs. Pre-conditioning of donor MSCs with S1P is an effective strategy to promote the therapeutic potential of MSCs for ischemic heart diseases. PMID: 30367841 [PubMed - in process]
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Related Articles Engineered Exosomes With Ischemic Myocardium-Targeting Peptide for Targeted Therapy in Myocardial Infarction. J Am Heart Assoc. 2018 Aug 07;7(15):e008737 Authors: Wang X, Chen Y, Zhao Z, Meng Q, Yu Y, Sun J, Yang Z, Chen Y, Li J, Ma T, Liu H, Li Z, Yang J, Shen Z Abstract Background Exosomes are membranous vesicles generated by almost all cells. Recent studies demonstrated that mesenchymal stem cell-derived exosomes possessed many effects, including antiapoptosis, anti-inflammatory effects, stimulation of angiogenesis, anticardiac remodeling, and recovery of cardiac function on cardiovascular diseases. However, targeting of exosomes to recipient cells precisely in vivo still remains a problem. Ligand fragments or homing peptides discovered by phage display and in vivo biopanning methods fused to the enriched molecules on the external part of exosomes have been exploited to improve the ability of exosomes to target specific tissues or organs carrying cognate receptors. Herein, we briefly elucidated how to improve targeting ability of exosomes to ischemic myocardium. Methods and Results We used technology of molecular cloning and lentivirus packaging to engineer exosomal enriched membrane protein (Lamp2b) fused with ischemic myocardium-targeting peptide CSTSMLKAC (IMTP). In vitro results showed that IMTP-exosomes could be internalized by hypoxia-injured H9C2 cells more efficiently than blank-exosomes. Compared with blank-exosomes, IMTP-exosomes were observed to be increasingly accumulated in ischemic heart area ( P<0.05). Meanwhile, attenuated inflammation and apoptosis, reduced fibrosis, enhanced vasculogenesis, and cardiac function were detected by mesenchymal stem cell-derived IMTP-exosome treatment in ischemic heart area. Conclusions Our research concludes that exosomes engineered by IMTP can specially target ischemic myocardium, and mesenchymal stem cell-derived IMTP-exosomes exert enhanced therapeutic effects on acute myocardial infarction. PMID: 30371236 [PubMed - in process]
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Related Articles Improving Gene Editing Outcomes in Human Hematopoietic Stem and Progenitor Cells by Temporal Control of DNA Repair. Stem Cells. 2018 Oct 29;: Authors: Lomova A, Clark DN, Campo-Fernandez B, Flores-Bjurström C, Kaufman ML, Fitz-Gibbon S, Wang X, Miyahira EY, Brown D, DeWitt MA, Corn JE, Hollis RP, Romero Z, Kohn DB Abstract Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated system (Cas9)-mediated gene editing of human hematopoietic stem cells (hHSCs) is a promising strategy for the treatment of genetic blood diseases through site-specific correction of identified causal mutations. However, clinical translation is hindered by low ratio of precise gene modification using the corrective donor template (homology-directed repair, HDR) to gene disruption (nonhomologous end joining, NHEJ) in hHSCs. By using a modified version of Cas9 with reduced nuclease activity in G1 phase of cell cycle when HDR cannot occur, and transiently increasing the proportion of cells in HDR-preferred phases (S/G2), we achieved a four-fold improvement in HDR/NHEJ ratio over the control condition in vitro, and a significant improvement after xenotransplantation of edited hHSCs into immunodeficient mice. This strategy for improving gene editing outcomes in hHSCs has important implications for the field of gene therapy, and can be applied to diseases where increased HDR/NHEJ ratio is critical for therapeutic success. Stem Cells 2018. PMID: 30372555 [PubMed - as supplied by publisher]
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Related Articles Cancer from the perspective of stem cells and misappropriated tissue regeneration mechanisms. Leukemia. 2018 Oct 30;: Authors: Ratajczak MZ, Bujko K, Mack A, Kucia M, Ratajczak J Abstract Tumorigenesis can be considered as pathologically misappropriated tissue regeneration. In this review we will address some unresolved issues that support this concept. First, we will address the issue of the identity of cancer-initiating cells and the presence of cancer stem cells in growing tumors. We will also ask are there rare and distinct populations of cancer stem cells in established tumor cell lines, or are all of the cells cancer stem cells? Second, the most important clinical problem with cancer is its metastasis, and here a challenging question arises: by employing radio-chemotherapy for tumor treatment, do we unintentionally create a prometastatic microenvironment in collateral organs? Specifically, many factors upregulated in response to radio-chemotherapy-induced injury may attract highly migratory cancer cells that survived initial treatment. Third, what is the contribution of normal circulating stem cells to the growing malignancy? Do circulating normal stem cells recognize a tumor as a hypoxia-damaged tissue that needs vascular and stromal support and thereby contribute to tumor expansion? Fourth, is it reasonable to inhibit only one prometastatic ligand-receptor axis when cancer stem cells express several receptors for several chemotactic factors that may compensate for inhibition of the targeted receptor? Fifth, since most aggressive cancer cells mimic early-development stem cells, which properties of embryonic stem cells are retained in cancer cells? Would it be reasonable to inhibit cancer cell signaling pathways involved in the migration and proliferation of embryonic stem cells? We will also briefly address some new players in cancerogenesis, including extracellular microvesicles, bioactive phospholipids, and extracellular nucleotides. PMID: 30375490 [PubMed - as supplied by publisher]
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Related Articles Evaluation of the impact of treatment with hematopoietic stem cells transplantation (HSCT) on biochemical markers of heart function and novel electrocardiographic markers of repolarization in patients with hematological malignancies. Med Oncol. 2018 Oct 31;35(12):162 Authors: Poręba M, Gać P, Usnarska-Zubkiewicz L, Pilecki W, Kuliczkowski K, Mazur G, Gonerska M, Sobieszczańska M, Poręba R Abstract High-dose chemotherapy (HDC) followed by stem cell transplantation (HSCT) is a well-established method in patients with hematological malignancies, and for last few years, many efforts have been made to estimate short- and long-term efficacy of this method, as well as early and late complications. The present study concentrates on cardiotoxic effects, mainly early changes using biochemical markers such as N-terminal natriuretic peptide type B (NT-proBNP) and cardiac troponins (cTn). Simultaneously, the analysis of 12-lead ECG was done before and after the procedure in which the novel repolarization markers: Tp-e and Tp-e/QT ratio were measured, together with standard markers: QT, QTc. It was found that NT-pro BNP was significantly increased after HSCT in comparison to results before it, and no significant changes were present in Troponin levels. Simultaneously, Tp-e interval and Tp-e/QT ratio were significantly higher after HSCT. The use of cyclophosphamide, advanced age, and higher level of blood cholesterol concentration were risk factors for the increase in NT-proBNP and treatment with cyclophosphamide as well as fludarabine and higher creatinine levels were risk factors for the increase in Tp-e/QT ratio. In conclusion, in the early term evaluation after HSCT in patients with no previously diagnosed heart disease, the mild changes in markers of heart overload and repolarization were noted. The observations suggest that in all patients undergoing HSCT, even the ones without pre-existing cardiovascular disease, the evaluation, and monitoring of heart function should be considered. PMID: 30382530 [PubMed - in process]
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Related Articles Therapeutic use of mesenchymal stem cell-derived extracellular vesicles in acute lung injury. Transfusion. 2018 Nov 01;: Authors: Lee JH, Park J, Lee JW Abstract Acute respiratory distress syndrome is a major cause of respiratory failure in critically ill patients. Despite extensive research into its pathophysiology, mortality remains high. No effective pharmacotherapy exists. Based largely on numerous preclinical animal studies, administration of mesenchymal stem or stromal cell (MSC) as a therapeutic for acute lung injury (ALI) holds great promise, and Phase I and II clinical trials are currently under way internationally. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, as well as the prohibitive cost of production, storage, and distribution of cells in bone marrow transplant facilities, may limit access to this lifesaving therapy. Accumulating evidence now suggest that novel stem cell-derived therapies, including MSC-conditioned medium and extracellular vesicles (EVs) released from MSCs, might constitute compelling alternatives. The current review summarizes the preclinical studies testing MSC EVs as treatment for ALI and other inflammatory lung diseases. While certain logistic obstacles limit the clinical applications of MSC-conditioned medium such as the volume required for treatment and lack of standardization of what constitutes the components of conditioned medium, the therapeutic application of MSC EVs remains promising, primarily due to ability of EVs to maintain the functional phenotype of the parent cell. However, utilization of MSC EVs will require large-scale production and standardization concerning identification, characterization, and quantification. PMID: 30383895 [PubMed - as supplied by publisher]
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Related Articles Integrated generation of induced pluripotent stem cells in a low-cost device. Biomaterials. 2019 Jan;189:23-36 Authors: Lin H, Li Q, Du Q, Wang O, Wang Z, Akert L, Carlson MA, Zhang C, Subramanian A, Zhang C, Lunning M, Li M, Lei Y Abstract Human induced pluripotent stem cells (iPSCs) have unlimited proliferation capability and potential to differentiate into all somatic cells. Their derivatives contain patients' genetic information and can model many diseases. Additionally, derivatives of patient-specific iPSCs induce minimal immune rejection in vivo. With this unique combination of properties, iPSCs open the avenue to personalized medicine including personalized drug screening, toxicity test, cell therapy and tissue engineering. However, the further advance of iPSC-based personalized medicine is currently limited by the difficulty to generate iPSCs for large populations and at affordable cost. We here report a low-cost device to address this challenge. The device allows the entire bioprocess for generating high quality and quantity of iPSCs for one patient to be done automatically within a closed conical tube without cell passaging. Additionally, iPSCs can be further differentiated into somatic cells in the device. Thus, the device also allows integrated iPSCs generation, expansion and differentiation to produce any somatic cell types. This device can be made in large quantities at low cost for manufacturing iPSCs (and their derivatives in necessary) for large populations at affordable cost. It will significantly advance the iPSCs-based personalized medicine. PMID: 30384126 [PubMed - in process]
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Related Articles Aryl hydrocarbon receptor mediates the cardiac developmental toxicity of EOM from PM2.5 in P19 embryonic carcinoma cells. Chemosphere. 2019 Feb;216:372-378 Authors: Chen T, Jin H, Wang H, Yao Y, Aniagu S, Tong J, Jiang Y Abstract Ambient fine particulate matter (PM2.5) has been found to be associated with congenital heart defects, but the molecular mechanisms remain to be elucidated. Our previous study revealed that extractable organic matter (EOM) from PM2.5 exerted cardiac developmental toxicity in zebrafish embryos. The aim of the current study is to explore the effects of EOM on cardiac differentiation of P19 mouse embryonic carcinoma stem cells. We found that EOM at 10 μg/ml (a non-cytotoxic dose level) significantly reduced the proportion of cardiac muscle troponin (cTnT) positive cells and the percentage of spontaneously beating embryoid bodies, indicating a severe inhibition of cardiac differentiation. Immunofluorescence and qPCR data demonstrated that EOM increased the expression levels of the aryl hydrocarbon receptor (AhR) and its target gene Cyp1A1 and diminished the expression level of β-catenin. Furthermore, EOM treatment significantly upregulated cell proliferation rate and elevated the percentage of γH2A.X positive cells without affecting apoptosis. It is worth noting that the EOM-induced changes in gene expression, cellular proliferation and DNA double strain breaks were attenuated by the AhR antagonist CH223191. In conclusion, our data indicate that AhR mediates the inhibitory effects of EOM (from PM2.5) on the cardiac differentiation of P19 cells. PMID: 30384306 [PubMed - in process]
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Related Articles Recent advances and challenges on application of tissue engineering for treatment of congenital heart disease. PeerJ. 2018;6:e5805 Authors: Mantakaki A, Fakoya AOJ, Sharifpanah F Abstract Congenital heart disease (CHD) affects a considerable number of children and adults worldwide. This implicates not only developmental disorders, high mortality, and reduced quality of life but also, high costs for the healthcare systems. CHD refers to a variety of heart and vascular malformations which could be very challenging to reconstruct the malformed region surgically, especially when the patient is an infant or a child. Advanced technology and research have offered a better mechanistic insight on the impact of CHD in the heart and vascular system of infants, children, and adults and identified potential therapeutic solutions. Many artificial materials and devices have been used for cardiovascular surgery. Surgeons and the medical industry created and evolved the ball valves to the carbon-based leaflet valves and introduced bioprosthesis as an alternative. However, with research further progressing, contracting tissue has been developed in laboratories and tissue engineering (TE) could represent a revolutionary answer for CHD surgery. Development of engineered tissue for cardiac and aortic reconstruction for developing bodies of infants and children can be very challenging. Nevertheless, using acellular scaffolds, allograft, xenografts, and autografts is already very common. Seeding of cells on surface and within scaffold is a key challenging factor for use of the above. The use of different types of stem cells has been investigated and proven to be suitable for tissue engineering. They are the most promising source of cells for heart reconstruction in a developing body, even for adults. Some stem cell types are more effective than others, with some disadvantages which may be eliminated in the future. PMID: 30386701 [PubMed]
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Related Articles Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits. Stem Cell Reports. 2018 Nov 13;11(5):1226-1243 Authors: Smith JGW, Owen T, Bhagwan JR, Mosqueira D, Scott E, Mannhardt I, Patel A, Barriales-Villa R, Monserrat L, Hansen A, Eschenhagen T, Harding SE, Marston S, Denning C Abstract Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations. PMID: 30392975 [PubMed - in process]
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Related Articles Stem cells as therapy for heart disease: iPSCs, ESCs, CSCs, and skeletal myoblasts. Biomed Pharmacother. 2018 Nov 02;109:304-313 Authors: Rikhtegar R, Pezeshkian M, Dolati S, Safaie N, Afrasiabi Rad A, Mahdipour M, Nouri M, Jodati AR, Yousefi M Abstract Heart Diseases are serious and global public health concern. In spite of remarkable therapeutic developments, the prediction of patients with Heart Failure (HF) is weak, and present therapeutic attitudes do not report the fundamental problem of the cardiac tissue loss. Innovative therapies are required to reduce mortality and limit or abolish the necessity for cardiac transplantation. Stem cell-based therapies applied to the treatment of heart disease is according to the understanding that natural self-renewing procedures are inherent to the myocardium, nonetheless may not be adequate to recover the infarcted heart muscle. Following the first account of cell therapy in heart diseases, examination has kept up to rapidity; besides, several animals and human clinical trials have been conducted to preserve the capacity of numerous stem cell population in advance cardiac function and decrease infarct size. The purpose of this study was to censoriously evaluate the works performed regarding the usage of four major subgroups of stem cells, including induced Pluripotent Stem Cells (iPSC), Embryonic Stem Cells (ESCs), Cardiac Stem Cells (CDC), and Skeletal Myoblasts, in heart diseases, at the preclinical and clinical studies. Moreover, it is aimed to argue the existing disagreements, unsolved problems, and prospect directions. PMID: 30396088 [PubMed - as supplied by publisher]
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Related Articles Enhancing Retention of Mesenchymal Stem Cells with Pro-survival Factors Promotes Angiogenesis in a Mouse Model of Limb Ischemia. Stem Cells Dev. 2018 Nov 06;: Authors: Cortez-Toledo E, Rose M, Agu E, Dahlenburg H, Yao W, Nolta JA, Zhou P Abstract Mesenchymal stem/stromal cells (MSCs) offer great promise in the treatment of ischemic injuries including stroke, heart infarction and limb ischemia. However, poor cell survival after transplantation remains a major obstacle to achieve effective MSC therapies. To improve cell survival and retention, we transplanted human bone marrow MSCs with or without a specific pro-survival factor (PSF) cocktail consisting of IGF1, Bcl-XL, a caspase inhibitor, a mitochondrial pathway inhibitor and matrigel into the limbs of immune deficient mice, after induction of hindlimb ischemia. The PSF markedly prolonged the retention of the MSCs in the ischemic limb muscles as demonstrated by bioluminescence imaging. Using micro-computed tomography (micro-CT) to image the limb muscle vasculature in the mice nine weeks after the transplantation, we found that the mice transplanted with MSCs without PSF did not show a significant increase in the blood vessels in the ischemic limb compared to the non-transplanted control mice. In contrast, the mice transplanted with MSCs plus PSF showed a significant increase in the blood vessels, especially the larger and branching vessels, in the ischemic limb as compared to the control mice that did not receive MSCs. Thus, we demonstrated that prolonged retention of MSCs using PSF effectively promoted angiogenesis in ischemic animal limbs. This study highlights the importance of enhancing cell survival in the development of effective MSC therapies to treat vascular diseases. PMID: 30398391 [PubMed - as supplied by publisher]
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Related Articles Adjunctive Use of Cidofovir and Intravenous Immunoglobulin to Treat Invasive Adenoviral Disease in Solid Organ Transplant Recipients. Pharmacotherapy. 2018 Nov 07;: Authors: Permpalung N, Mahoney MV, Alonso CD Abstract BACKGROUND: Infections with adenoviruses (ADVs) can result in considerable mortality and morbidity in solid organ transplant (SOT) recipients. Standard therapy for ADV infections in transplant recipients is not established. At our institution, intravenous cidofovir and immunoglobulin have been used to treat disseminated or invasive ADV in SOT and hematopoietic stem cell transplant recipients. METHODS: A retrospective case series of SOT recipients treated with cidofovir and intravenous immunoglobulin was performed. RESULTS: Five SOT recipients (four renal and one heart transplant) with adenovirus infection were treated successfully with cidofovir and immunoglobulin. Cidofovir was discontinued after the first negative ADV viral load and resolution of clinical symptoms, given the concern for nephrotoxicity in renal transplant recipients. Renal tubular acidosis type 2 and iritis were observed in two patients receiving therapy. CONCLUSION: Symptom resolution and a single negative ADV viral load may be indicators for cidofovir discontinuation. PMID: 30403300 [PubMed - as supplied by publisher]
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Related Articles Human NK Cells Develop an Exhaustion Phenotype During Polar Degranulation at the Aspergillus fumigatus Hyphal Synapse. Front Immunol. 2018;9:2344 Authors: Santiago V, Rezvani K, Sekine T, Stebbing J, Kelleher P, Armstrong-James D Abstract Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of A. fumigatus. We show that the in vitro interaction between NK cells and A. fumigatus induces partial activation of NK cell immune response, characterised by low-level production of IFN-γ, TNF-α, MIP-1α, MIP-1β, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact-dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine-mediated response to leukaemic cells was impaired in the presence of A. fumigatus. These observations suggest that A. fumigatus-mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis. PMID: 30405602 [PubMed - in process]
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Related Articles Resistin promotes cardiac homing of mesenchymal stem cells and functional recovery after myocardial ischemia/reperfusion via the ERK1/2-MMP-9 pathway. Am J Physiol Heart Circ Physiol. 2018 Nov 09;: Authors: He Y, Guo Y, Xia Y, Guo Y, Wang R, Zhang F, Guo L, Liu Y, Yin T, Gao C, Gao E, Li C, Wang S, Zhang L, Yan W, Tao L Abstract BACKGROUND: Stem cell therapy is a potentially effective and promising treatment for ischemic heart disease. Resistin, a type of adipokine, has been found to bind to adipose-derived mesenchymal stem cells (ADSCs). However, the effects of resistin on cardiac homing by ADSCs and on ADSC-mediated cardioprotective effects have not been investigated. METHODS: ADSCs were obtained from EGFP transgenic mice. C57BL/6J mice were subjected to myocardial ischemia/reperfusion (I/R) or sham operations. Six hours after the I/R operation, mice were intravenously injected with resistin-treated ADSCs (ADSC-resistin) or vehicle-treated ADSCs (ADSC-vehicle). Cardiac homing by ADSCs and cardiomyocyte apoptosis were investigated 3 days after I/R. Cardiac function, fibrosis, and angiogenesis were evaluated 4 weeks after I/R. Cellular and molecular mechanisms were investigated in vitro using cultured ADSCs. RESULTS: Both immunostaining and flow cytometric studies showed that resistin treatment promoted ADSC myocardial homing 3 days after intravenous injection. Echocardiographic studies showed that ADSC-resistin, but not ADSC-vehicle, significantly improved the left ventricular ejection fraction (LVEF). ADSC-resistin transplantation significantly mitigated I/R-induced fibrosis and reduced ANP/BNP mRNA expression. In addition, cardiomyocyte apoptosis was reduced while angiogenesis was increased by ADSC-resistin treatment. At the cellular level, resistin promoted ADSC proliferation and migration, but did not affect H2O2-induced apoptosis. Molecular studies identified the ERK1/2-MMP-9 pathway as a key component mediating the effects of resistin on ADSC proliferation and migration. CONCLUSION: These results demonstrate that resistin can promote homing of injected ADSCs into damaged heart tissue and stimulate functional recovery, an effect mediated through the ERK1/2 signaling pathway and MMP-9. PMID: 30412442 [PubMed - as supplied by publisher]
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Related Articles Progress and Challenge of Cardiac Regeneration to Treat Heart Failure. J Cardiol. 2018 Nov 09;: Authors: Isomi M, Sadahiro T, Ieda M Abstract Cardiac muscle has limited proliferative capacity, and regenerative therapies are highly in demand as a new treatment strategy. Pharmacological and non-pharmacological therapies have been developed, but these medical therapies have limited effects to cure patients with severe heart failure. Moreover, heart transplantation is limited due to the low number of donor organs. Thus, heart regeneration holds great potential to offer innovative therapy to treat heart failure patients. Currently, there are several strategies for heart regeneration. Transplantation of somatic stem cells was safe and modestly improved cardiac function after myocardial infarction mainly through paracrine mechanisms. Alternatively, new cardiomyocytes could be generated from induced pluripotent stem cells (iPSCs) to transplant into injured hearts. However, several issues remain to be resolved prior to using iPSC-derived cardiomyocytes, such as a potential risk of tumorigenesis and poor survival of transplanted cells in the injured heart. More recently, direct cardiac reprogramming has emerged as a novel technology to regenerate damaged myocardium by directly converting endogenous cardiac fibroblasts into induced cardiomyocyte-like cells to restore cardiac function. Following our first report of cardiac reprogramming, an improvement in cardiac reprogramming efficiency, in vivo direct cardiac reprogramming, and cardiac reprogramming in human cells were reported by many investigators. While these previous studies have advanced regenerative research, many challenges remain. Here, we review the current status of cardiac regenerative technology, a great hope to treat cardiovascular diseases. PMID: 30420106 [PubMed - as supplied by publisher]
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Related Articles Stem cell banking: Are South Indian mothers aware? Cell Tissue Bank. 2018 Dec;19(4):791-798 Authors: Rajendran S, Kirubhakaran A, Alaudheen R, Jayaramayya K, Santhanakalai M, Jayaraman S, Chinnaraju S, Reddy JK, Vellingiri B Abstract Umbilical cord blood (UCB) is an important source of stem cells, the heart of regenerative medicine. As the globalization and population of the world continues to increase, we are faced with an inundation of new diseases, affecting millions of people. Research work considering stem cells is essential for developing therapy for various conditions. Reduced availability of UCB serves as a hindrance to promote further research. Hence, India being one of the most densely populated countries in the world, can be considered a potential UCB repository. In this study 428 mothers of children born in the period from 2012 to 2017 were asked to fill questionnaires that evaluated their awareness regarding stem cell banking. This investigation deliberates if expectant mothers in this region are aware of stem cell banking and if there is a significant pattern regarding awareness based on parameters like age, educational qualification, locality, annual income and consulted hospitals. Although, majority of the women were unaware of this facility, knowledge was heightened in wealthy, educated, women from urban areas who consulted private hospitals. Hence, great efforts need to be made to further the awareness of expectant mothers in South India regarding UCB storage and donation. PMID: 30421273 [PubMed - in process]
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Related Articles Brief topical sodium nitrite and its impact on the quality of life in patients with sickle leg ulcers. Medicine (Baltimore). 2018 Nov;97(46):e12614 Authors: Connor JL, Sclafani JA, Kato GJ, Hsieh MM, Minniti CP Abstract Cutaneous ulceration from sickle cell disease negatively impacts quality of life. Topical sodium nitrite has previously been shown to reduce the size of sickle leg ulcers. This study examined how topical sodium nitrite impacted the quality of life scores in patients with sickle leg ulcers.We prospectively collected data in patients enrolled in a leg ulcer study (n = 17) or an allogeneic hematopoietic cell transplant study (nonulcer group, n = 15). Both groups completed a pretreatment Short Form-36 questionnaire; the ulcer group completed a second questionnaire after 4 weeks of topical sodium nitrite applications. Data were analyzed by age, sex, >50% area improvement postintervention, and sickle-related complications (vaso-occlusive crises, pulmonary hypertension, or avascular necrosis). Physical and mental component summary scores were analyzed with Student t test.Physical summary scores were lower than mental summary scores in all groups, indicating leg ulcers among other sickle related complications negatively impacted physical quality of life measures. After sodium nitrite use, physical summary scores improved in the leg ulcer group (34.5 ± 9.4 to 39 ± 10.3, P = .03), and mental summary scores improved more in ulcerated patients ≤35 years old (40.7 ± 6.9 to 51.7 ± 9.7, P = .01).Brief topical sodium nitrite has the potential to improve quality of life, especially in younger individuals. Longer treatment duration and randomized-controlled trials are needed to confirm the efficacy of this topical therapy. PMID: 30431560 [PubMed - indexed for MEDLINE]
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Related Articles Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1617-1629 Authors: Ladenstein R, Pötschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chan GCF, Ruud E, Schroeder H, Beck Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN Abstract BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer. PMID: 30442501 [PubMed - in process]
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Related Articles Low plasma stem cell factor combined with high transforming growth factor-α identifies high-risk patients in pulmonary arterial hypertension. ERJ Open Res. 2018 Oct;4(4): Authors: Bouzina H, Rådegran G Abstract In pulmonary arterial hypertension (PAH), severe vasoconstriction and remodelling of small pulmonary arteries result in high mortality. Receptor tyrosine kinases and their ligands, such as transforming growth factor (TGF)-α, modulate proliferation in PAH. Although the receptor tyrosine kinase c-Kit has been shown to be overexpressed in PAH, the expression and role of its ligand stem cell factor (SCF) remain unknown. However, low plasma SCF levels are known to be linked to higher cardiovascular mortality risk. Using proximity extension assays, we measured SCF and TGF-α in venous plasma from treatment-naïve PAH patients and healthy controls. Patients were stratified into risk classes based on PAH guidelines. Plasma SCF was decreased (p=0.013) and TGF-α was increased (p<0.0001) in PAH patients compared to controls. SCF correlated to pulmonary vascular resistance (r=-0.66, p<0.0001), cardiac index (r=0.66, p<0.0001), venous oxygen saturation (r=0.47, p<0.0008), mean right atrial pressure (r=-0.44, p<0.002) and N-terminal pro-brain natriuretic protein (r=-0.39, p<0.006). SCF was lower in "high-risk" compared to "intermediate-risk" (p=0.0015) or "low-risk" (p=0.0009) PAH patients. SCF and TGF-α levels combined (SCF/TGF-α) resulted in 85.7% sensitivity and 81.5% specificity for detecting high-risk patients (p<0.0001). Finally, REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) risk scores in PAH patients correlated to SCF/TGF-α levels (r=-0.50, p=0.0003). In conclusion, low plasma SCF combined with high TGF-α identifies high-risk PAH patients at baseline. Lower circulating SCF levels, which are associated with worse haemodynamics, may be related to the c-Kit accumulation previously observed in PAH. PMID: 30443557 [PubMed]
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Related Articles Studies on the effects of microencapsulated human mesenchymal stem cells in RGD-modified alginate on cardiomyocytes under oxidative stress conditions using in vitro biomimetic co-culture system. Int J Biol Macromol. 2018 Nov 13;123:512-520 Authors: Choe G, Park J, Jo H, Kim YS, Ahn Y, Lee JY Abstract Stem cell therapy has been recognized as a promising approach for myocardium regeneration post myocardial infarction (MI); however, it unfortunately often remains a challenge because of poor survival of transplanted cells and a lack of clear understanding of their interactions with host cells. High oxidative stress at heart tissues post MI is considered one of the important factors damaging transplanted cells and native cells/tissues. Here, we employed an in vitro co-culture system, capable of mimicking cases of stem cell transplantation into the myocardium presenting high oxidative stress, using human mesenchymal stem cells (hMSCs) encapsulated in alginate or cell interactive Arg-Gly-Asp (RGD) peptide-modified alginate micro-hydrogels. Under H2O2-induced oxidative stress conditions, viabilities of hMSCs and CMs were significantly higher in their co-culture than in their individual monolayer cultures. Expression of cardiac muscle markers remained high even with H2O2 treatment when cardiomyocytes (CMs) were co-cultured with hMSCs in RGD-alginate. Higher levels of various growth factors (associated with angiogenesis, cardiac regeneration, and contractility) were found in co-culture (noticeably with RGD-alginate) compared to monolayer cultures of CMs or hMSCs. These results can benefit the study of in vivo MI progression with transplanted stem cells and the development of effective stem cell-based therapeutic strategies for various oxidative stress-related diseases. PMID: 30445088 [PubMed - as supplied by publisher]
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Related Articles Wharton' jelly mesenchymal stromal cell therapy for ischemic brain injury. Brain Circ. 2018 Jul-Sep;4(3):124-127 Authors: Wu KJ, Yu SJ, Chiang CW, Lee YW, Yen BL, Hsu CS, Kuo LW, Wang Y Abstract Increasing evidence have supported that Wharton's jelly mesenchymal stem cell (WJ-MSCs) have immunomodulatory and protective effects against several diseases including kidney, liver pathologies, and heart injury. Few in vitro studies have reported that WJ-MSCs reduced inflammation in hippocampal slices after oxygen-glucose deprivation. We recently reported the neuroprotective effects of human WJ-MSCs (hWJ-MSCs) in rats exposed to a transient right middle cerebral artery occlusion. hWJ-MSCs transplantation significantly reduced brain infarction and microglia activation in the penumbra leading with a significant reduction of neurological deficits. Interestingly, the grafted hWJ-MSCs in the ischemic core were mostly incorporated into IBA1 (+) cells, suggesting that hWJ-MSCs were immunorejected by the host. The immune rejection of hWJ-MSCs was reduced in after cyclosporine A treatment. Moreover, the glia cell line-derived neurotrophic factor expression was significantly increased in the host brain after hWJ-MSCs transplantation. In conclusion, these results suggest that the protective effect of hWJ-MSCs may be due to the secretion of trophic factors rather than to the survival of grafted cells. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences. PMID: 30450419 [PubMed]
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Related Articles Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering. Cell Mol Life Sci. 2018 Nov 20;: Authors: Ellis MW, Luo J, Qyang Y Abstract Elastin-associated vasculopathies are life-threatening conditions of blood vessel dysfunction. The extracellular matrix protein elastin endows the recoil and compliance required for physiologic arterial function, while disruption of function can lead to aberrant vascular smooth muscle cell proliferation manifesting through stenosis, aneurysm, or vessel dissection. Although research efforts have been informative, they remain incomplete as no viable therapies exist outside of a heart transplant. Induced pluripotent stem cell technology may be uniquely suited to address current obstacles as these present a replenishable supply of patient-specific material with which to study disease. The following review will cover the cutting edge in vascular smooth muscle cell modeling of elastin-associated vasculopathy, and aid in the development of human disease modeling and drug screening approaches to identify potential treatments. Vascular proliferative disease can affect up to 50% of the population throughout the world, making this a relevant and critical area of research for therapeutic development. PMID: 30460472 [PubMed - as supplied by publisher]
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Related Articles Role of Stem Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Pulmonary Emphysema. COPD. 2018 Nov 23;:1-21 Authors: Coppolino I, Ruggeri P, Nucera F, Cannavò MF, Adcock I, Girbino G, Caramori G Abstract There are only few human translational studies performed in the area of stem cell research in patients with chronic obstructive pulmonary disease (COPD) and/or pulmonary emphysema. Before progress to clinical trials with stem cells we strongly believe that more human translational studies are essential, otherwise, the clinical rationale would be solely based on limited in vitro and animal studies. In the future, stem cell therapy could be a treatment for this incurable disease. As of now, stem cell therapy is still to be considered as an area of active research, lacking any strong rationale for performing clinical trials in COPD. Although stem cells would be likely to represent a heterogeneous population of cells, the different cell subsets and their importance in the pathogenesis of the different clinical phenotypes need to be fully characterised before progressing to clinical trials. Moreover, the potential side effects of stem cell therapy are underestimated. We should not ignore that some of the most deadly neoplasms are arising from stem cells. PMID: 30468084 [PubMed - as supplied by publisher]
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Related Articles Biomaterials for Stem Cell Therapy for Cardiac Disease. Adv Exp Med Biol. 2018;1064:181-193 Authors: Kim H, Kim SL, Choi YH, Ahn YH, Hwang NS Abstract Myocardial Infarction (MI) in cardiac disease is the result of heart muscle losses due to a wide range of factors. Cardiac muscle failure is a crucial condition that provokes life-threatening outcomes. Heretofore, regeneration therapies in MI have used stem-cell-based therapy instantly after a myocardial injury to prevent the disease process and tissue malfunction. Despite the therapeutic utility of stem-cell-based regenerative therapy, barriers to successful treatment have been addressed. In this chapter, we illustrate a variety of emerging biomaterial strategies for enhancing the function of therapeutic stem cells, such as cell surface modification to synthetically endowing stem cells with new characteristics and hydrogels with its biological and mechanical properties. These investments offer a potential accompaniment to traditional stem-cell-based therapies for enhancing the efficacy of stem cell therapy to design properly activating cardiac tissues. PMID: 30471033 [PubMed - in process]
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Related Articles Daratumumab, pomalidomide, and dexamethasone as a bridging therapy to autologous stem cell transplantation in a case of systemic light-chain amyloidosis with advanced cardiac involvement. J Oncol Pharm Pract. 2018 Nov 26;:1078155218815305 Authors: Arnall JR, Usmani SZ, Adamu H, Mishkin J, Bhutani M Abstract Systemic light-chain (AL) amyloidosis is a rare hematologic disorder where proteins infiltrate tissues leading to organ failure and death. Cardiac involvement, present in ∼70% of patients, determines stage and prognosis of the disease, with advanced involvement having a median survival of six months. The treatment of light-chain amyloidosis is directed at recovering organ function with therapeutic strategies following those of multiple myeloma with plasma cell-directed therapies. The use of single agent daratumumab has been reported in light-chain amyloidosis achieving rapid and deep responses. The combination of daratumumab, pomalidomide, and dexamethasone (DaraPomD) is particularly interesting for severe AL based on success in multiple myeloma. A 43-year-old female with light-chain amyloidosis and concomitant multiple myeloma presented with severe bowel dysmotility causing abdominal pain, anemia, and a 100-pound unintentional weight loss. A combination of cyclophosphamide, bortezomib, and dexamethasone was initiated but after five cycles her symptoms were progressing and therapy was switched to DaraPomD to optimize response. At the conclusion of two cycles she had achieved an amyloid complete-hematologic response, with her recurring ileus and abdominal pain significantly improved. Additionally, cardiac markers also suggested a rapid response without a common paradoxical worsening of congestive heart failure, and was overall well tolerated. Given the severe symptoms and refractory nature of our patient's disease DaraPomD was reasonable. With the tolerability and response seen, this patient experience supports a formal clinical trial evaluating the safety and efficacy of DaraPomD in light-chain amyloidosis. PMID: 30477388 [PubMed - as supplied by publisher]
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Related Articles Mesenchymal Stem Cell Therapy for Aging Frailty. Front Nutr. 2018;5:108 Authors: Schulman IH, Balkan W, Hare JM Abstract Chronic diseases and degenerative conditions are strongly linked with the geriatric syndrome of frailty and account for a disproportionate percentage of the health care budget. Frailty increases the risk of falls, hospitalization, institutionalization, disability, and death. By definition, frailty syndrome is characterized by declines in lean body mass, strength, endurance, balance, gait speed, activity and energy levels, and organ physiologic reserve. Collectively, these changes lead to the loss of homeostasis and capability to withstand stressors and resulting vulnerabilities. There is a strong link between frailty, inflammation, and the impaired ability to repair tissue injury due to decreases in endogenous stem cell production. Although exercise and nutritional supplementation provide benefit to frail patients, there are currently no specific therapies for frailty. Bone marrow-derived allogeneic mesenchymal stem cells (MSCs) provide therapeutic benefits in heart failure patients irrespective of age. MSCs contribute to cellular repair and tissue regeneration through their multilineage differentiation capacity, immunomodulatory, and anti-inflammatory effects, homing and migratory capacity to injury sites, and stimulatory effect on endogenous tissue progenitors. The advantages of using MSCs as a therapeutic strategy include standardization of isolation and culture expansion techniques and safety in allogeneic transplantation. Based on this evidence, we performed a randomized, double-blinded, dose-finding study in elderly, frail individuals and showed that intravenously delivered allogeneic MSCs are safe and produce significant improvements in physical performance measures and inflammatory biomarkers. We thus propose that frailty can be treated and the link between frailty and chronic inflammation offers a potential therapeutic target, addressable by cell therapy. PMID: 30498696 [PubMed]
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Related Articles Emerging therapeutic targets for metabolic syndrome: lessons from animal models. Endocr Metab Immune Disord Drug Targets. 2018 Nov 30;: Authors: Singh H, Pragasam SJ, Venkatesan V Abstract INTRODUCTION: Metabolic syndrome is a cluster of medical conditions that synergistically increase the risk of heart diseases, and diabetes. The current treatment strategy for metabolic syndrome focuses on treating its individual components. A highly effective agent for metabolic syndrome has yet to be developed. To develop target for metabolic syndrome the mechanism encompassing different organs - nervous system, pancreas, skeletal muscle, liver and adipose tissue - needs to be understood. Many animal models have been developed to understand the pathophysiology of metabolic syndrome. Promising molecular targets have emerged while characterizing these animals. Modulating these targets is expected to treat some components of metabolicsyndrome. OBJECTIVE: To discuss the emerging molecular targets in animal model of metabolic syndrome. METHOD: A literature search was performed for the retrieval of relevant articles. CONCLUSION: Multiple genes/pathways that play important role in the development of Metabolic Syndrome are discussed. PMID: 30499422 [PubMed - as supplied by publisher]
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Related Articles Therapeutic applications of adipose-derived stem cells in cardiovascular disease. Am J Stem Cells. 2018;7(4):94-103 Authors: Bruun K, Schermer E, Sivendra A, Valaik E, Wise RB, Said R, Bracht JR Abstract Cardiovascular disease (CVD) is the number one cause of death globally, and new therapeutic techniques outside of traditional pharmaceutical and surgical interventions are currently being developed. At the forefront is stem cell-centered therapy, with adipose derived stem cells (ADSCs), an adult stem population, providing significant clinical promise. When introduced into damaged heart tissue, ADSCs promote cardiac regeneration by a variety of mechanisms including differentiation into new cardiomyocytes and secretion of paracrine factors acting on endogenous cardiac cells. We discuss the application of ADSCs, their biochemical capabilities, availability, ease of extraction, clinical trial results, and areas of concern. The multipotent capacity of ADSCs along with their ability to secrete factors promoting cell survival and regeneration, along with their immunosuppressive capacity, make them an extremely promising approach in the field of CVD therapy. PMID: 30510844 [PubMed]
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Related Articles Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair. ACS Nano. 2018 Dec 04;: Authors: Li Z, Shen D, Hu S, Su T, Huang K, Liu F, Hou L, Cheng K Abstract Stem cell therapy is one of the promising strategies for the treatment of ischemic heart disease. However, the clinical application of stem cells transplantation is limited by low cell engraftment in the infarcted myocardium. Taking advantage of pretargeting and bioorthogonal chemistry, we engineered a pretargeting and bioorthogonal chemistry (PTBC) system to capture endogenous circulating stem cells and target them to the injured heart for effective repair. Two bioorthogonal antibodies were i.v. administrated with a pretargeting interval (48 h). Through bioorthogonal click reaction, the two antibodies are linked in vivo, engaging endogenous stem cells with circulating platelets. As a result, the platelets redirect the stem cells to the injured heart. In vitro and in vivo studies demonstrated that bioorthogonal click reaction was able to induce the conjugation of platelets and endothelial progenitor cells (EPCs) and enhance the binding of EPCs to collagen and injured blood vessels. More importantly, in a mouse model of acute myocardial infarction, the in vivo results of cardiac function, heart morphometry, and immunohistochemistry assessment all confirmed effective heart repair by the PTBC system. PMID: 30511851 [PubMed - as supplied by publisher]
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Related Articles In vitro and in vivo Proteomic Comparison of Human Neural Progenitor Cell-Induced Photoreceptor Survival. Proteomics. 2018 Dec 04;:e1800213 Authors: Jones MK, Lu B, Chen DZ, Spivia WR, Mercedo A, Ljubimov AV, Svendsen CN, Van Eyk JE, Wang S Abstract Retinal degenerative diseases are some of the leading causes of blindness with few treatments. Various cell-based therapies have aimed to slow the progression of vision loss by preserving light-sensing photoreceptor cells. A subretinal injection of human neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) rat model of retinal degeneration has aided in photoreceptor survival, though the mechanisms are mainly unknown. Identifying the retinal proteomic changes that occur following hNPC treatment will lead to better understanding of neuroprotection. To mimic the retinal environment following hNPC injection, a co-culture system of retinas and hNPCs was developed. Less cell death occurred in RCS retinal tissue co-cultured with hNPCs than in retinas cultured alone, suggesting that hNPCs provide retinal protection in vitro. Comparison of ex vivo and in vivo retinas identified NRF2-mediated oxidative response signaling as an hNPC-induced pathway. This is the first study to compare proteomic changes following treatment with hNPCs in both an ex vivo and in vivo environment, further allowing the use of ex vivo modeling for mechanisms of retinal preservation. Elucidation of the protein changes in the retina following hNPC treatment may lead to the discovery of mechanisms of photoreceptor survival and its therapeutic for clinical applications. This article is protected by copyright. All rights reserved. PMID: 30515959 [PubMed - as supplied by publisher]
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Engineered Heart Slice Model of Arrhythmogenic Cardiomyopathy using Plakophilin-2 Mutant Myocytes. Tissue Eng Part A. 2018 Dec 06;: Authors: Blazeski A, Lowenthal J, Wang Y, Teuben R, Zhu R, Gerecht S, Tomaselli G, Tung L Abstract Arrhythmogenic cardiomyopathy (AC), a cause of sudden cardiac death among young and otherwise healthy individuals, is a heritable disease that can be modeled in vitro using patient-specific cardiac myocytes (CMs) from induced pluripotent stem cells. An understanding of underlying disease mechanisms, particularly in the early concealed stages, could lead to new diagnosis and treatment strategies. However, multicellular syncytial models are needed to understand how genetically-encoded mutations of the desmosomes that interconnect cells lead to aberrant electrical conduction and arrhythmias. Here, engineered heart slices (EHS) were created by seeding human induced pluripotent stem cell-derived CMs from an AC patient with a plakophilin-2 (PKP2) mutation onto intact slices of decellularized myocardium and then compared to age-matched AC CMs cultured as monolayers. After 2 weeks of culture, EHS developed into a confluent, multilayered syncytia that exhibited spontaneous, coordinated beating and could be electrically paced at cycle lengths ranging from 2000ms to 500ms. AC CMs cultured as EHS displayed highly aligned, dense, and ordered sarcomeric structures, with gene expression analyses revealing increased maturation. Additionally, AC-relevant genes were affected by CM culture in EHS, with a substantial increase in PPARG and a decrease in SCN5A when compared to monolayers. Functionally, AC EHS exhibited similar conduction velocities, shorter action potentials, and a slower and steadier spontaneous beat rate compared with monolayers. Reentrant arrhythmias could also be induced in AC EHS by S1-S2 pacing. Our findings suggest that the EHS microenvironment enhances the phenotype of AC CMs in culture while allowing for functional studies of an appropriately aligned syncytium of AC-CMs. Results reported here demonstrate the benefits of studying AC using EHS, a tissue construct that allows syncytial culture and the incorporation of matrix cues. PMID: 30520705 [PubMed - as supplied by publisher]
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