Liver Disease and Stem Cell Therapy at SIRM
What is Liver Disease?
The liver is under your ribs on the right hand side. The liver is the largest organ in the body and if the liver fails completely then untreated only 3-4 days to find a donor liver for a possible transplant.
Corrently there is no such thing as an artificial liver.
The liver not only produces many proteins it creates energy from our food. The liver removes waste products in our body and also removes unwanted drugs such as nicotine and alcohol.
The most common Liver conditions include infections such as hepatitis A, B, C, E, alcohol damage, fatty liver, cirrhosis, cancer, drug damage especially paracetamol (acetaminophen) and cancer drugs.
The liver does not have any pain nerves so liver disease can be unexpected.
Liver disease is commonly related to alcohol and diet problems.
STEM CELL RESEARCH
Use of hepatocyte and stem cells for treatment of post-resectional liver failure: are we there yet?
Ezzat TM, Dhar DK, Newsome PN, Malagó M, Olde Damink SW.
2011 Jul;31(6):773-84. doi: 10.1111/j.1478-3231.2011.02530.x. Epub 2011 Apr 19.
HPB and Liver Transplantation Surgery, Royal Free Hospital, University College London, Pond Street, London, UK.
Post-operative liver failure following extensive resections for liver tumours is a rare but significant complication. The only effective treatment is liver transplantation (LT); however, there is a debate about its use given the high mortality compared with the outcomes of LT for chronic liver diseases.
Cell therapy has emerged as a possible alternative to LT especially as endogenous hepatocyte proliferation is likely inhibited in the setting of prior chemo/radiotherapy. Both hepatocyte and stem cell transplantations have shown promising results in the experimental setting; however, there are few reports on their clinical application.
This review identifies the potential stem cell sources in the body, and highlights the triggering factors that lead to their mobilization and integration in liver regeneration following major liver resections.
Therapeutic plasticity of stem cells and allograft tolerance.
Cytotherapy. 2011 May 10;
Authors: Sordi V, Piemonti L
Abstract Transplantation is the treatment of choice for many diseases that result in organ failure, but its success is limited by organ rejection. Stem cell therapy has emerged in the last years as a promising strategy for the induction of tolerance after organ transplantation. Here we discuss the ability of different stem cell types, in particular mesenchymal stromal cells, neuronal stem/progenitor cells, hematopoietic stem cells and embryonic stem cells, to modulate the immune response and induce peripheral or central tolerance.
These stem cells have been studied to explore tolerance induction to several transplanted organs, such as heart, liver and kidney. Different strategies, including approaches to generating tolerance in islet transplantation, are discussed here.
PMID: 21554176 [PubMed - as supplied by publisher]
Impaired function of bone marrow-derived endothelial progenitor cells in murine liver fibrosis.
Biosci Trends. 2011 Apr;5(2):77-82
Authors: Shirakura K, Masuda H, Kwon SM, Obi S, Ito R, Shizuno T, Kurihara Y, Mine T, Asahara T
Liver fibrosis (LF) caused by chronic liver damage has been considered as an irreversible disease. As alternative therapy for liver transplantation, there are high expectations for regenerative medicine of the liver.
Bone marrow (BM)- or peripheral blood-derived stem cells, including endothelial progenitor cells (EPCs), have recently been used to treat liver cirrhosis. We investigated the biology of BM-derived EPC in a mouse model of LF. C57BL/6J mice were subcutaneously injected with carbon tetrachloride (CCl4) every 3 days for 90 days. Sacrificed 2 days after final injection, whole blood (WB) was collected for isolation of mononuclear cells (MNCs) and biochemical examination.
Assessments of EPC in the peripheral blood and BM were performed by flow cytometry and EPC colonyforming assay, respectively, using purified MNCs and BM c-KIT+, Sca-1+, and Lin- (KSL) cells.
Liver tissues underwent histological analysis with hematoxylin/eosin/Azan staining, and spleens were excised and weighed. CCl4-treated mice exhibited histologically bridging fibrosis, pseudolobular formation, and splenomegaly, indicating successful induction of LF.
The frequency of definitive EPC-colony-forming-units (CFU) as well as total EPC-CFU at the equivalent cell number of 500 BM-KSL cells decreased significantly (p < 0.0001) in LF mice compared with control mice; no significant changes in primitive EPC-CFU occurred in LF mice.
The frequency of WB-MNCs of definitive EPC-CFU decreased significantly (p < 0.01) in LF mice compared with control mice. Together, these findings indicated the existence of impaired EPC function and differentiation in BM-derived EPCs in LF mice and might be related to clinical LF.
PMID: 21572251 [PubMed - in process]
Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling.
Related Articles Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling. Cell Rep. 2016 05 10;15(6):1175-89 Authors: Lau EY, Lo J, Cheng BY, Ma MK, Lee JM, Ng JK, Chai S, Lin CH, Tsang SY, Ma S, Ng IO, Lee TK Abstract Like normal stem cells, tumor-initiating cells (T-ICs) are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs) would regulate liver T-ICs. We found that the presence of α-SMA(+) CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC. PMID: 27134167 [PubMed - indexed for MEDLINE]Read more...
CELL THERAPY FOR GI MOTILITY DISORDERS: COMPARISON OF CELL SOURCES AND PROPOSED STEPS FOR TREATING HIRSCHSPRUNG DISEASE.
Related Articles CELL THERAPY FOR GI MOTILITY DISORDERS: COMPARISON OF CELL SOURCES AND PROPOSED STEPS FOR TREATING HIRSCHSPRUNG DISEASE. Am J Physiol Gastrointest Liver Physiol. 2017 Feb 16;:ajpgi.00018.2017 Authors: Stamp LA Abstract Cell therapeutic approaches to treat a range of congenital and degenerative neuropathies are under intense investigation. There have been recent significant advancements in the development of cell therapy to treat disorders of the enteric nervous system, enteric neuropathies. These advances include the efficient generation of enteric neural progenitors from pluripotent stem cells and the rescue of a Hirschsprung Disease model mouse following their transplantation into the bowel. Further, a recent study provides evidence of functional innervation of the bowel muscle by neurons derived from transplanted ENS-derived neural progenitors. This mini-review discusses these recent findings, compares endogenous ENS-derived progenitors and pluripotent stem cell-derived progenitors as a cell source for therapy, and proposes the key steps for cell therapy to treat Hirschsprung Disease. PMID: 28209600 [PubMed - as supplied by publisher]Read more...
Noninvasive imaging of human immune responses in a human xenograft model of graft-versus-host disease.
Related Articles Noninvasive imaging of human immune responses in a human xenograft model of graft-versus-host disease. J Nucl Med. 2017 Feb 16;: Authors: Van Elssen CH, Rashidian M, Vrbanac V, Wucherpfennig KW, El Habre Z, Sticht J, Freund C, Jacobsen J, Cragnolini J, Ingram J, Plaisier L, Spierings E, Tager AM, Ploegh H Abstract The immune system plays a crucial role in many diseases. Activation or suppression of immunity is often related to clinical outcome. Methods to explore the dynamics of immune responses are important to elucidate their role in conditions characterized by inflammation, such as infectious disease, cancer or auto-immunity. Immuno-PET is a non-invasive method by which disease and immune cell infiltration can be explored simultaneously. Using radiolabeled antibodies or fragments derived from them, it is possible to image disease-specific antigens and immune cell subsets. We aimed to develop a method to noninvasively image human immune responses in a relevant humanized mouse model. We developed a camelid-derived single domain antibody (VHH) specific for human class II MHC products and used it to non-invasively image human immune cell reconstitution in NSG (NOD-scid gamma) mice reconstituted with human fetal thymus, liver and liver-derived hematopoitic stem cells (BLT mice). We show imaging of infiltrating immunocytes in BLT mice that spontaneously develop a graft versus host (GvHD)-like condition, characterized by alopecia, blepharitis and target organ infiltration by activated human T cells. In diseased animals, we show an increased PET signal in the liver, attributable to infiltration of activated Class II MHC-positive T cells. Non-invasive imaging of immune infiltration and activation could thus be of importance for diagnosis and evaluation of treatment of GvHD and holds promise for other diseases characterized by inflammation. PMID: 28209904 [PubMed - as supplied by publisher]Read more...
Related Articles Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases. Biomed Res Int. 2017;2017:8910821 Authors: Kholodenko IV, Yarygin KN Abstract The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable. PMID: 28210629 [PubMed - in process]Read more...
The Effect of the Human Peptide GHK on Gene Expression Relevant to Nervous System Function and Cognitive Decline.
The Effect of the Human Peptide GHK on Gene Expression Relevant to Nervous System Function and Cognitive Decline. Brain Sci. 2017 Feb 15;7(2): Authors: Pickart L, Vasquez-Soltero JM, Margolina A Abstract Neurodegeneration, the progressive death of neurons, loss of brain function, and cognitive decline is an increasing problem for senior populations. Its causes are poorly understood and therapies are largely ineffective. Neurons, with high energy and oxygen requirements, are especially vulnerable to detrimental factors, including age-related dysregulation of biochemical pathways caused by altered expression of multiple genes. GHK (glycyl-l-histidyl-l-lysine) is a human copper-binding peptide with biological actions that appear to counter aging-associated diseases and conditions. GHK, which declines with age, has health promoting effects on many tissues such as chondrocytes, liver cells and human fibroblasts, improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, boney tissue), increases collagen, decorin, angiogenesis, and nerve outgrowth, possesses anti-oxidant, anti-inflammatory, anti-pain and anti-anxiety effects, increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Studies using the Broad Institute Connectivity Map show that GHK peptide modulates expression of multiple genes, resetting pathological gene expression patterns back to health. GHK has been recommended as a treatment for metastatic cancer, Chronic Obstructive Lung Disease, inflammation, acute lung injury, activating stem cells, pain, and anxiety. Here, we present GHK's effects on gene expression relevant to the nervous system health and function. PMID: 28212278 [PubMed]Read more...