Multiple Sclerosis Stem Cell Treatment

Multiple Sclerosis and Stem Cell Therapy

What is MS?

Multiple Sclerosis and Stem Cell Treatment

Multiple Sclerosis and Stem Cell Therapy

Multiple sclerosis is also known as disseminated sclerosis or encephalomyelitis disseminata.

It is an inflammatory disease where the fatty myelin sheaths around the axons of the brain and spinal cord are damaged. The disease often leads to demyelination and scarring.

The disease usually appears in young adults and is more common in women. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other.

Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin.

In MS, the body's own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals.

The name multiple sclerosis refers to scars (scleroses—better known as plaques or lesions) particularly in the white matter of the brain and spinal cord, which is mainly composed of myelin.

Although much is known about the mechanisms involved in the disease process, the cause remains unknown. There is currently no known cure for multiple sclerosis and treatments attempt to return function after an attack, prevent new attacks, and prevent disability.

 

Multiple Sclerosis and Stem Cell Therapy

Immune Reconstitution after Double Umbilical Cord Blood Stem Cell Transplantation: Comparison with Unrelated Peripheral Blood Stem Cell Transplantation.


2011 Aug 26. [Epub ahead of print]

Jacobson CA, Turki AT, McDonough SM, Stevenson KE, Kim HT, Kao G, Herrera MI, Reynolds CG, Alyea EP, Ho VT, Koreth J, Armand P, Chen YB, Ballen K, Soiffer RJ, Antin JH, Cutler CS, Ritz J.


Source Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.


Abstract
Double umbilical cord blood (DUCB) transplantation is an accepted transplantation strategy for patients without suitable human leukocyte antigen (HLA) matched donors. However, DUCB transplantation is associated with increased morbidity and mortality because of slow recovery of immunity and a high risk of infection. To define the differences in immune reconstitution between DUCB transplantation and HLA matched unrelated donor (MUD) transplantation, we performed a detailed, prospective analysis of immune reconstitution in 42 DUCB recipients and 102 filgrastim-mobilized unrelated peripheral blood stem cell recipients.

Reconstitution of CD3 T cells was significantly delayed in the DUCB cohort compared with the MUD cohort for 1 to 6 months posttransplantation (P < .001), including naive (CD45RO-) and memory (CD45RO+) CD4 T cells, regulatory (CD4CD25) T cells, and CD8 T cells. In contrast, CD19 B cells recovered more rapidly in the DUCB cohort and numbers remained significantly greater from 3 to 24 months after transplantation (P = .001).

CD56CD16 natural killer (NK) cells also recovered more rapidly in DUCB recipients and remained significantly greater from 1 to 24 months after transplantation. B cell activating factor (BAFF) levels were higher in the DUCB cohort at 1 month (P < .001), were similar in both cohorts at 3 and 6 months, and were lower in the DUCB cohort at 12 months (P = .002). BAFF/CD19 B cell ratios were lower in the DUCB cohort at 3 (P = .045), 6 (P = .02), and 12 months (P = .002) after transplantation. DUCB recipients had more infections within the first 100 days after transplantation (P < .001), and there was less chronic graft-versus-host disease (P < .001), but there were no differences in cumulative incidence of relapse, nonrelapse death, progression-free survival, or overall survival between the 2 groups. These results suggest that increased risk of infections is specifically associated with delayed reconstitution of all major T cell subsets, but the increased risk is limited to the first 3 months after DUCB transplantation. There is no increased risk of relapse, suggesting that graft-versus-leukemia activity is maintained. Early reconstitution of B cells and NK cells may, in part, account for these findings.


PMID: 21875503 [PubMed - as supplied by publisher]

 

Adult stem cells and multiple sclerosis.

Cell Prolif. 2011 Apr;44 Suppl 1:35-8

Authors: Scolding N

Multiple sclerosis (MS) is a common neurological disease and a major cause of disability, particularly affecting young adults.

It is characterized by patches of damage occurring throughout the brain and spinal cord, with loss of myelin sheaths - the insulating material around nerve fibres that allows normal conduction of nerve impulses - accompanied by loss of cells that make myelin (oligodendrocytes).

 

In addition, we now know that there is damage to nerve cells (neurones) and their fibres (axons) too, and that this occurs both within these discrete patches and in tissue between them. The cause of MS remains unknown, but an autoimmune reaction against oligodendrocytes and myelin is generally assumed to play a major role, and early acute MS lesions almost invariably show prominent inflammation.

Efforts to develop cell therapy in MS have long been directed towards directly implanting cells capable of replacing lost oligodendrocytes and regenerating myelin sheaths.

Accordingly, the advent of techniques to generate large numbers of oligodendrocytes from embryonic stem cells appeared a significant step towards new stem cell treatments for MS; while the emerging consensus that adult stem cells from, for example, the bone marrow had far less potential to turn into oligodendrocytes was thought to cast doubt on their potential value in this disease.

A number of scientific and medical concerns, not least the risk of tumour formation associated with embryonic stem cells, have however, prevented any possible clinical testing of these cells in patients.

 

More recently, increasing understanding of the complexity of tissue damage in MS has emphasized that successful cell therapy may need to achieve far more than simply offering a source of replacement myelin-forming cells.

The many and varied reparative properties of bone marrow-derived (mesenchymal) stem cells may well offer new and attractive possibilities for developing cell-based treatments for this difficult and disabling condition.

PMID: 21481041 [PubMed - in process]

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Related Articles Primary progressive multiple sclerosis: progress and challenges. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1100-6 Authors: Rice CM, Cottrell D, Wilkins A, Scolding NJ Abstract Primary progressive multiple sclerosis (MS) has long been recognised as presenting great difficulties to our management of what is increasingly a treatable neurological disease. Here we review some basic and clinical aspects of primary progressive MS, and describe how the disorder in fact offers powerful insights and opportunities for better understanding multiple sclerosis, and from a practical perspective an invaluable clinical substrate for studying and treating progressive disability in MS. Difficult hurdles remain, however, and these too are reviewed. PMID: 23418213 [PubMed - indexed for MEDLINE]
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Related Articles Neuro-immune interactions of neural stem cell transplants: From animal disease models to human trials. Exp Neurol. 2013 Mar 16; Authors: Giusto E, Donegà M, Cossetti C, Pluchino S Abstract Stem cell technology is a promising branch of regenerative medicine that is aimed at developing new approaches for the treatment of severely debilitating human diseases, including those affecting the central nervous system (CNS). Despite the increasing understanding of the mechanisms governing their biology, the application of stem cell therapeutics remains challenging. The initial idea that stem cell transplants work in vivo via the replacement of endogenous cells lost or damaged owing to disease has been challenged by accumulating evidence of their therapeutic plasticity. This new concept covers the remarkable immune regulatory and tissue trophic effects that transplanted stem cells exert at the level of the neural microenvironment to promote tissue healing via combination of immune modulatory and tissue protective actions, while retaining predominantly undifferentiated features. Among a number of promising candidate stem cell sources, neural stem/precursor cells (NPCs) are under extensive investigation with regard to their therapeutic plasticity after transplantation. The significant impact in vivo of experimental NPC therapies in animal models of inflammatory CNS diseases has raised great expectations that these stem cells, or the manipulation of the mechanisms behind their therapeutic impact, could soon be translated to human studies. This review aims to provide an update on the most recent evidence of therapeutically-relevant neuro-immune interactions following NPC transplants in animal models of multiple sclerosis, cerebral stroke and traumas of the spinal cord, and consideration of the forthcoming challenges related to the early translation of some of these exciting experimental outcomes into clinical medicines. PMID: 23507035 [PubMed - as supplied by publisher]
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Related Articles Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis. J Neurosci. 2013 Apr 3;33(14):5980-91 Authors: Lin W, Lin Y, Li J, Fenstermaker AG, Way SW, Clayton B, Jamison S, Harding HP, Ron D, Popko B Abstract There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. Moreover, there is evidence that PERK signaling is activated in oligodendrocytes within demyelinating lesions in multiple sclerosis and EAE. Our previous study demonstrated that CNS delivery of the inflammatory cytokine interferon-γ before EAE onset protected mice against EAE, and this protection was dependent on PERK signaling. In our current study, we sought to elucidate the role of PERK signaling in oligodendrocytes during EAE. We generated transgenic mice that allow for temporally controlled activation of PERK signaling, in the absence of ER stress, specifically in oligodendrocytes. We demonstrated that persistent activation of PERK signaling was not deleterious to oligodendrocyte viability or the myelin of adult animals. Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE. PMID: 23554479 [PubMed - indexed for MEDLINE]
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Related Articles Towards clinical application of mesenchymal stem cells for treatment of neurological diseases of the central nervous system. J Neuroimmune Pharmacol. 2013 Dec;8(5):1062-76 Authors: Laroni A, Novi G, Kerlero de Rosbo N, Uccelli A Abstract The diagnosis of a neurological disease of the central nervous system (CNS) is often associated with the anticipation of an irreversible and untreatable disability. This is the case also of multiple sclerosis (MS) where approved treatments effectively modulate the autoimmune attack to myelin antigens, but poorly affect neurodegeneration and do not promote tissue repair. Thus, stem cell-based therapies are increasingly being considered a possible strategy for diseases of the CNS. Mesenchymal stem cells (MSC), the safety of which has been demonstrated in the last 20 years through clinical trials and case studies, are of particular interest in view not only of their neuroprotective, but also of their immunomodulatory properties. Here, we review the therapeutic features of MSC that make them relevant in the treatment of CNS illnesses and discuss the pioneer clinical experience with MSC-based therapy in neurological diseases. PMID: 23579931 [PubMed - in process]
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Related Articles Large-scale production of human mesenchymal stem cells for clinical applications. Biotechnol Appl Biochem. 2012 Mar-Apr;59(2):106-20 Authors: Jung S, Panchalingam KM, Wuerth RD, Rosenberg L, Behie LA Abstract Human mesenchymal stem cells (hMSCs) have many potential applications in tissue engineering and regenerative medicine. Currently, hMSCs are generated through conventional static adherent cultures in the presence of fetal bovine serum (FBS) for clinical applications (e.g., multiple sclerosis). However, these methods are not appropriate to meet the expected future demand for quality-assured hMSCs for human therapeutic use. Hence, it is imperative to develop an effective hMSC production system, which should be controllable, reproducible, and scalable. To this end, efforts have been made by several international research groups to develop (i) alternative media either by replacing FBS with human-sourced supplements (such as human serum or platelet lysate) or by identifying defined serum-free formulations consisting of key growth/attachment factors, and (ii) controlled bioreactor protocols. In this regard, we review here current hMSC production technologies and future perspectives toward efficient methods for the generation of clinically relevant numbers of hMSC therapeutics. PMID: 23586791 [PubMed - indexed for MEDLINE]
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Related Articles Management of secondary progressive multiple sclerosis: prophylactic treatment-past, present, and future aspects. Curr Treat Options Neurol. 2013 Jun;15(3):241-58 Authors: Rommer PS, Stüve O Abstract OPINION STATEMENT: Whereas the number of treatment options in relapsing-remitting multiple sclerosis (RRMS) is growing constantly, alternatives are rare in the case of secondary-progressive multiple sclerosis (SPMS). Besides mitoxantrone in North America and Europe, interferon beta-1b and beta-1a are approved for treatment in Europe. Glucocorticosteroids, azathioprine, intravenous immunoglobulins (IVIG) and cyclophosphamide (CYC), although not approved, are commonly utilized in SPMS. Currently monoclonal antibodies (mab), and masitinib are under examination for treatment for SPMS. Hematopoietic stem cell transplantation and immunoablative stem cell transplantation are therapies with the aim of reconstitution of the immune system. This review gives information on the different therapeutics and the trials that tested them. Pathophysiological considerations are presented in view of efficacy of the therapeutics. In addition, therapeutics that showed no efficacy in trials or with unacceptable side effects are topics of this review. PMID: 23609781 [PubMed]
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Related Articles Hematopoietic stem cell transplantation in multiple sclerosis. Expert Rev Neurother. 2013 May;13(5):567-78 Authors: Karussis D, Petrou P, Vourka-Karussis U, Kassis I Abstract It is widely accepted that the main common pathogenetic pathway in multiple sclerosis (MS) involves an immune-mediated cascade initiated in the peripheral immune system and targeting CNS myelin. Logically, therefore, therapeutic approaches to the disease include modalities aiming at downregulation of the various immune elements that are involved in this immunological cascade. Since the introduction of interferons in 1993, more specific immunoactive drugs have been introduced, but still most of them can, at best, effectively modulate only the early relapsing phases of MS. The more progressed phases of the disease are not efficiently amendable by the existing immunomodulatory drugs. Moreover, localized and compartmentized inflammation in the CNS, which seems to be mostly responsible for the chronic axonal damage and resulting progression of disability, is less affected by the current drugs. A more radical approach to suppress all the inflammation in MS, including that into the CNS, could theoretically be achieved with high-dose immunosuppression using strong cytotoxic medications and resetting of the immune system by hematopoietic stem cell transplantation (HSCT). HSCT, both allogeneic and autologous, has been tried as a novel therapeutic approach in various autoimmune diseases. During the last 15 years several (mostly open) clinical studies evaluated the effect of HSTC on MS patients; the published papers showed that a high proportion of the HSCT-treated MS patients were stabilized, or even improved after the transplantation and have generally indicated a beneficial effect on disease progression. In this review, the rationale of HSCT and the summary of the results of the existing clinical trials are presented. Despite the fact that it is difficult to collectively summarize the results of all the trials, due to lack of uniformity in the conditioning and treatment protocols and of completed controlled studies, these clinical studies have provided a strong 'proof of concept' for HSCT in MS and have significantly contributed to our understanding of the advantages and disadvantages of each approach and HSCT protocol. PMID: 23621313 [PubMed - indexed for MEDLINE]
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Related Articles Human embryonic stem cell-derived oligodendrocytes: protocols and perspectives. Stem Cells Dev. 2013 Sep 15;22(18):2459-76 Authors: Alsanie WF, Niclis JC, Petratos S Abstract Oligodendrocytes play a fundamental supportive role in the mammalian central nervous system (CNS) as the myelinating-glial cells. Disruption of fast axonal transport mechanisms can occur as a consequence of mature oligodendrocyte loss following spinal cord injury, stroke, or due to neuroinflammatory conditions, such as multiple sclerosis. As a result of the limited remyelination ability in the CNS after injury or disease, human embryonic stem cells (hESCs) may prove to be a promising option for the generation and replacement of mature oligodendrocytes. Moreover, hESC-derived oligodendrocytes may be experimentally utilized to unravel fundamental questions of oligodendrocyte development, along with their therapeutic potential through growth factor support of axons and neurons. However, an intensive characterization and examination of hESC-derived oligodendrocytes prior to preclinical or clinical trials is required to facilitate greater success in their integration following cellular replacement therapy (CRT). Currently, the protocols utilized to derive oligodendrocytes from hESCs consist of significant variations in culture style, time-length of differentiation, and the provision of growth factors in culture. Further, these differing protocols also report disparate patterns in the expression of oligodendroglial markers by these derived oligodendrocytes, throughout their differentiation in culture. We have comprehensively reviewed the published protocols describing the derivation of oligodendrocytes from hESCs and the studies that examine their efficacy to remyelinate, along with the fundamental issues of their safety as a viable CRT. Additionally, this review will highlight particular issues of concern and suggestions for troubleshooting to provide investigators critical information for the future improvement of establishing in vitro hESC-derived oligodendrocytes. PMID: 23621561 [PubMed - indexed for MEDLINE]
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Related Articles Inflammatory, vascular, and infectious myelopathies in children. Handb Clin Neurol. 2013;112:999-1017 Authors: Verhey LH, Banwell BL Abstract Acute nontraumatic myelopathies of childhood include inflammatory, infectious, and vascular etiologies. Inflammatory immune-mediated disorders of the spinal cord can be categorized as idiopathic isolated transverse myelitis, neuromyelitis optica, and multiple sclerosis. In recent years, human T-cell lymphotropic virus type 1, West Nile virus, enterovirus-71, and Lyme disease have been increasingly recognized as infectious etiologies of myelopathy, and poliomyelitis remains an important etiology in world regions where vaccination programs have not been universally available. Vascular etiologies include vasculopathies (systemic lupus erythematosus, small vessel primary angiitis of the central nervous system), arteriovenous malformations, and spinal cord infarction (fibrocartilaginous embolism, diffuse hypoxic ischemia-mediated infarction). Vascular myelopathies are less common than inflammatory and infectious myelopathies, but are more likely to lead to devastating clinical deficits. Current therapeutic strategies include acute anti-inflammatory treatment and rehabilitation. Stem cell transplantation, nerve graft implantation, and stimulation of endogenous repair mechanisms represent promising strategies for spinal cord repair. PMID: 23622308 [PubMed - indexed for MEDLINE]
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Related Articles Autologous hematopoietic stem cell transplantation as a treatment option for aggressive multiple sclerosis. Curr Treat Options Neurol. 2013 Jun;15(3):270-80 Authors: Pfender N, Saccardi R, Martin R Abstract OPINION STATEMENT: Despite the development of several injectable or oral treatments for relapsing-remitting multiple sclerosis (RRMS), it remains difficult to treat patients with aggressive disease, and many of these continue to develop severe disability. During the last two decades autologous hematopoietic stem cell transplantation (aHSCT) has been explored with the goal to eliminate an aberrant immune system and then re-install a healthy and tolerant one from hematopoietic precursor cells that had been harvested from the patient prior to chemotherapy. Clinical studies have shown that aHSCT is able to completely halt disease activity in the majority of patients with aggressive RRMS. Research on the mechanisms of action supports that aHSCT indeed leads to renewal of a healthy immune system. Below we will summarize important aspects of aHSCT and mention the currently best-examined regimen. PMID: 23637027 [PubMed]
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Related Articles Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr Mol Med. 2013 Jun;13(5):856-67 Authors: Stagg J, Galipeau J Abstract Cell therapy with mesenchymal stromal cells (MSCs) is the focus of intensive investigation. Several clinical trials, including large-scale placebo-controlled phase III clinical trials, are currently underway evaluating the therapeutic potential of autologous and allogeneic MSCs for treatment of catastrophic inflammatory diseases, including steroid-refractory graft-versus-host disease (GvHD), multiple sclerosis (MS) and Crohn's disease. MSCs are also being investigated as carriers of anti-cancer biotherapeutics. We here review recent developments in our understanding of the immunosuppressive properties of MSCs. We firstly discuss the effects of ex vivo culture conditions on the phenotype and functions of MSCs. Secondly, we summarize the immune functions suppressed by MSCs with a focus on T cell, B cell, natural killer cell and dendritic cell functions. Thirdly, we discuss newly identified pathways responsible for the immunosuppressive activity of MSCs, including the expression of heme-oxygenase (HO)-1, the secretion of galectins, CCL2 antagonism, T regulatory cell (Treg) cross-talk and production of TNF-α stimulated gene/protein-6 (TSG-6). Finally, we review the literature on the molecular pathways governing MSC homing and discuss recent clinical data on the use of MSCs for treatment of GvHD, MS and Crohn's disease. PMID: 23642066 [PubMed - indexed for MEDLINE]
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Related Articles Investigation of sequential growth factor delivery during cuprizone challenge in mice aimed to enhance oligodendrogliogenesis and myelin repair. PLoS One. 2013;8(5):e63415 Authors: Sabo JK, Aumann TD, Kilpatrick TJ, Cate HS Abstract Repair in multiple sclerosis involves remyelination, a process in which axons are provided with a new myelin sheath by new oligodendrocytes. Bone morphogenic proteins (BMPs) are a family of growth factors that have been shown to influence the response of oligodendrocyte progenitor cells (OPCs) in vivo during demyelination and remyelination in the adult brain. We have previously shown that BMP4 infusion increases numbers of OPCs during cuprizone-induced demyelination, while infusion of Noggin, an endogenous antagonist of BMP4 increases numbers of mature oligodendrocytes and remyelinated axons following recovery. Additional studies have shown that insulin-like growth factor-1 (IGF-1) promotes the survival of OPCs during cuprizone-induced demyelination. Based on these data, we investigated whether myelin repair could be further enhanced by sequential infusion of these agents firstly, BMP4 to increase OPC numbers, followed by either Noggin or IGF-1 to increase the differentiation and survival of the newly generated OPCs. We identified that sequential delivery of BMP4 and IGF-1 during cuprizone challenge increased the number of mature oligodendrocytes and decreased astrocyte numbers following recovery compared with vehicle infused mice, but did not alter remyelination. However, sequential delivery of BMP4 and Noggin during cuprizone challenge did not alter numbers of oligodendrocytes or astrocytes in the corpus callosum compared with vehicle infused mice. Furthermore, electron microscopy analysis revealed no change in average myelin thickness in the corpus callosum between vehicle infused and BMP4-Noggin infused mice. Our results suggest that while single delivery of Noggin or IGF-1 increased the production of mature oligodendrocytes in vivo in the context of demyelination, only Noggin infusion promoted remyelination. Thus, sequential delivery of BMP4 and Noggin or IGF-1 does not further enhance myelin repair above what occurs with delivery of Noggin alone. PMID: 23650566 [PubMed - indexed for MEDLINE]
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Related Articles Twenty years of experience on stem cell transplantation in iran. Iran Red Crescent Med J. 2013 Feb;15(2):93-100 Authors: Ghavamzadeh A, Alimoghaddam K, Ghaffari F, Derakhshandeh R, Jalali A, Jahani M Abstract BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a new window to therapy of many diseases. From March 1991 through April 2011, a total of 3237 HSCT were performed in the Hematology-Oncology and Stem Cell Transplantation Research Center, affiliated to Tehran University of Medical Sciences. Here we report 20 years experience of HSCT. OBJECTIVES: Our strategy and aim include the protraction of cytogenetic and molecular biological diagnostic tests, the expansion of the first Iranian Cord Blood Bank (ICBB) and development of the first Iranian Stem Cell Donor Program (ISCDP), and improvement the researches in new therapeutic fields. PATIENTS AND METHODS: Totally, 3237 patients were undergone HSCT. Of these transplants, 2205 were allogeneic stem cell transplantation, 1016 autologous and 16 syngeneic. Among 2205 patients who were undergone allogenic-HSCT, 34 received cord blood stem cells as stem cell source for transplantation. It is important to point out that cord blood bank at our center provides reliable storage of cord blood stem cells for our patients. Stem cell transplantation was performed for treatment of various diseases such as acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphoblastic leukemia, beta-thalassemia major, sickle- cell thalassemia, sickle- cell disease, multiple myeloma, myelodysplasia, mucopolysaccharidosis, paroxysmal nocturnal hemoglobinuria, non-Hodgkin's lymphoma, Hodgkin's disease, severe aplastic anemia, plasma cell leukemia, Niemann-Pick disease, Fanconi anemia, severe combined immunodeficiency, congenital neutropenia, leukocyte adhesion deficiencies, Chediak-Higashi syndrome, osteopetrosis, histiocytosis X, Hurler syndrome, amyloidosis, systemic sclerosis, breast cancer, Ewing's sarcoma, testicular cancer, germ cell tumors, neuroblastoma, medulloblastoma, renal cell carcinoma, nasopharyngeal carcinoma, ovarian cancer, Wilms' tumor, rhabdomyosarcoma, pancreatoblastoma, and multiple sclerosis. Also, we had 220 cellular therapies for post-myocardial infarction, multiple sclerosis, cirrhosis, head of femur necrosis, Diabetes Mellitus and GvHD treatment. 45 patients were undergone retransplantation in this center. RESULTS: About 78.2% of the patients (2530 of 3237) remained alive between one to 211 months after stem cell transplantation. Nearly, 21.8% (707) of our patients died after stem cell transplantation. The main causes of death were relapse, infection, hemorrhagic cystitis, graft-versus- host disease and etc. CONCLUSIONS: In Iran, HSCT has been successfully adapted in routine clinical care. Recently, new methods such as double cord blood and haploidentical transplantation have been used to treat many life-threatening diseases. PMID: 23682320 [PubMed]
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Related Articles The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 2013 Jun;24(3):203-15 Authors: Vincent FB, Saulep-Easton D, Figgett WA, Fairfax KA, Mackay F Abstract The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials. PMID: 23684423 [PubMed - indexed for MEDLINE]
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Related Articles Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells. Arch Med Res. 2013 May;44(4):266-72 Authors: Mohyeddin Bonab M, Mohajeri M, Sahraian MA, Yazdanifar M, Aghsaie A, Farazmand A, Nikbin B Abstract BACKGROUND AND AIMS: Mesenchymal stem cells (MSC) are currently strong candidates for stem cell therapy. Cytokines have a profound effect on the resultant immune responses. This study aims to evaluate variations in the cytokine profile of multiple sclerosis patients treated with autologous MSC. METHODS: Twenty five patients received one dose of intrathecal MSCs (mean number: 29.5 × 10⁶). To measure the gene expression of FOXP3, IFN-γ, TGF-β, IL-4, IL-10, IL-6, and their serum proteins, samples were collected at five intervals: day 0 prior to injection and months 1, 3, 6, and 12 after MSC therapy. Gene expression was evaluated via real-time PCR and protein values were measured by ELISA. RESULTS: There were no statistically significant variations in gene expression and serum level of cytokines after a 1-year follow-up of MSC-treated MS patients. The only correlation found was an increase in IL-6 gene expression in patients with progressive disease. CONCLUSION: Intrathecal injection of MSCs does not affect cytokine variation in peripheral blood. Because the condition of most of our patients either improved or stabilized after stem cell therapy (SCT), we speculate that the immunomodulatory or neuroregenerative effects of MSC are exerted locally in the central nervous system. PMID: 23684533 [PubMed - indexed for MEDLINE]
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Related Articles Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor. Scand J Immunol. 2013 Aug;78(2):214-20 Authors: Shamim Z, Spellman S, Haagenson M, Wang T, Lee SJ, Ryder LP, Müller K Abstract Interleukin-7 (IL-7) is essential for T cell development in the thymus and maintenance of peripheral T cells. The α-chain of the IL-7R is polymorphic with the existence of SNPs that give rise to non-synonymous amino acid substitutions. We previously found an association between donor genotypes and increased treatment-related mortality (TRM) (rs1494555G) and acute graft versus host disease (aGvHD) (rs1494555G and rs1494558T) after hematopoietic cell transplantation (HCT). Some studies have confirmed an association between rs6897932C and multiple sclerosis. In this study, we evaluated the prognostic significance of IL-7Rα SNP genotypes in 590-recipient/donor pairs that received HLA-matched unrelated donor HCT for haematological malignancies. Consistent with the primary studies, the rs1494555GG and rs1494558TT genotypes of the donor were associated with aGvHD and chronic GvHD in the univariate analysis. The Tallele of rs6897932 was suggestive of an association with increased frequency of relapse by univariate analysis (P = 0.017) and multivariate analysis (P = 0.015). In conclusion, this study provides further evidence of a role of the IL-7 pathway and IL-7Rα SNPs in HCT. PMID: 23692589 [PubMed - indexed for MEDLINE]
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Related Articles Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 May;14 Suppl 1:19-32 Authors: Turner MR, Bowser R, Bruijn L, Dupuis L, Ludolph A, McGrath M, Manfredi G, Maragakis N, Miller RG, Pullman SL, Rutkove SB, Shaw PJ, Shefner J, Fischbeck KH Abstract The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery. PMID: 23678877 [PubMed - indexed for MEDLINE]
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Related Articles Gene therapy of multiple sclerosis using interferon β-secreting human bone marrow mesenchymal stem cells. Biomed Res Int. 2013;2013:696738 Authors: Ryu CH, Park KY, Hou Y, Jeong CH, Kim SM, Jeun SS Abstract Interferon-beta (IFN- β ), a well-established standard treatment for multiple sclerosis (MS), has proved to exhibit clinical efficacy. In this study, we first evaluated the therapeutic effects for MS using human bone marrow-derived mesenchymal stem cells (hBM-MSCs) as delivery vehicles with lesion-targeting capability and IFN- β as therapeutic gene. We also engineered hBM-MSCs to secret IFN- β (MSCs-IFN β ) via adenoviral transduction and confirmed the secretory capacity of MSCs-IFN β by an ELISA assay. MSCs-IFN β -treated mice showed inhibition of experimental autoimmune encephalomyelitis (EAE) onset, and the maximum and average score for all animals in each group was significantly lower in the MSCs-IFN β -treated EAE mice when compared with the MSCs-GFP-treated EAE mice. Inflammatory infiltration and demyelination in the lumbar spinal cord also significantly decreased in the MSCs-IFN β -treated EAE mice compared to PBS- or MSCs-GFP-treated EAE mice. Moreover, MSCs-IFN β treatment enhanced the immunomodulatory effects, which suppressed proinflammatory cytokines (IFN-γ and TNF-α) and conversely increased anti-inflammatory cytokines (IL-4 and IL-10). Importantly, injected MSCs-IFN β migrated into inflamed CNS and significantly reduced further injury of blood-brain barrier (BBB) permeability in EAE mice. Thus, our results provide the rationale for designing novel experimental protocols to enhance the therapeutic effects for MS using hBM-MSCs as an effective gene vehicle to deliver the therapeutic cytokines. PMID: 23710456 [PubMed - indexed for MEDLINE]
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Related Articles T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis. Immunology. 2013 Oct;140(2):211-9 Authors: Burman J, Fransson M, Tötterman TH, Fagius J, Mangsbo SM, Loskog AS Abstract Autologous haematopoietic stem cell transplantation (HSCT) for relapsing-remitting multiple sclerosis is a potentially curative treatment, which can give rise to long-term disease remission. However, the mode of action is not yet fully understood. The aim of the study was to evaluate similarities and differences of the CD4(+) T-cell populations between HSCT-treated patients (n = 12) and healthy controls (n = 9). Phenotyping of memory T cells, regulatory T (Treg) cells and T helper type 1 (Th1) and type 17 (Th17) cells was performed. Further, T-cell reactivity to a tentative antigen, myelin oligodendrocyte glycoprotein, was investigated in these patient populations. Patients treated with natalizumab (n = 15) were included as a comparative group. White blood cells were analysed with flow cytometry and T-cell culture supernatants were analysed with magnetic bead panel immunoassays. HSCT-treated patients had similar levels of Treg cells and of Th1 and Th17 cells as healthy subjects, whereas natalizumab-treated patients had lower frequencies of Treg cells, and higher frequencies of Th1 and Th17 cells. Cells from HSCT-treated patients cultured with overlapping peptides from myelin oligodendrocyte glycoprotein produced more transforming growth factor-β1 than natalizumab-treated patients, which suggests a suppressive response. Conversely, T cells from natalizumab-treated patients cultured with those peptides produced more interleukin-17 (IL-17), IL-1 and IL-10, indicating a Th17 response. In conclusion, we demonstrate circumstantial evidence for the removal of autoreactive T-cell clones as well as development of tolerance after HSCT. These results parallel the long-term disease remission seen after HSCT. PMID: 23721329 [PubMed - indexed for MEDLINE]
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Related Articles The road to remyelination in demyelinating diseases: current status and prospects for clinical treatment. Expert Rev Clin Immunol. 2013 Jun;9(6):535-49 Authors: Wootla B, Watzlawik JO, Denic A, Rodriguez M Abstract Within CNS disorders, demyelinating diseases are among the most devastating and cost intensive due to long-term disabilities affecting relatively young patients. Multiple sclerosis, a chronic inflammatory demyelinating disease in which the persistent inhibitory microenvironment of the resident oligodendrocyte precursor cells abrogates regeneration of myelin sheaths, is the most prominent disease in the spectrum of demyelinating diseases. The essential goal is to stimulate creation of new myelin sheaths on the demyelinated axons, leading to restoration of saltatory conduction and resolving functional deficits. The past few decades witnessed significant efforts to understand the cellular interactions at the lesion site with studies suggesting efficient remyelination as a prerequisite for functional repair. Despite its proven efficacy in experimental models, immunosuppression has not had profound clinical consequences in multiple sclerosis, which argued for a paradigm shift in the design of therapeutics aiming to achieve remyelination. For example, targeting oligodendrocytes themselves may drive remyelination in the CNS. This group and others have demonstrated that natural autoreactive antibodies directed at oligodendrocyte progenitors participate in remyelination. Accordingly, the authors developed a recombinant autoreactive natural human IgM antibody with therapeutic potential for remyelination. PMID: 23730884 [PubMed - indexed for MEDLINE]
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Related Articles Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole. J Neurophysiol. 2013 Sep;110(5):1047-61 Authors: Bellingham MC Abstract Riluzole is the sole treatment for amyotrophic lateral sclerosis (ALS), but its therapeutically relevant actions on motor neurons are not well defined. Whole cell patch-clamp recordings were made from hypoglossal motor neurons (HMs, n = 25) in brain stem slices from 10- to 23-day-old rats anesthetized with pentobarbital sodium to investigate the hypothesis that riluzole inhibits HMs by multiple mechanisms. Riluzole (20 μM) hyperpolarized HMs by decreasing an inward current, inhibited voltage-gated persistent Na(+) and Ca(2+) currents activated by slow voltage ramps, and negatively shifted activation of the hyperpolarization-activated cationic current (IH). Repetitive firing of HMs was strongly inhibited by riluzole, which also increased action potential threshold voltage and rheobase and decreased amplitude and maximum rise slope but did not alter the maximal afterhyperpolarization amplitude or decay time constant. HM rheobase was inversely correlated with persistent Na(+) current density. Glutamatergic synaptic transmission was inhibited by riluzole by both pre- and postsynaptic effects. Riluzole decreased activity-dependent glutamate release, as shown by decreased amplitude of evoked and spontaneous excitatory postsynaptic currents (EPSCs), decreased paired-pulse ratio, and decreased spontaneous, but not miniature, EPSC frequency. However, riluzole also decreased miniature EPSC amplitude and the inward current evoked by local application of glutamate onto HMs, suggesting a reduction of postsynaptic glutamate receptor sensitivity. Riluzole thus has a marked inhibitory effect on HM activity by membrane hyperpolarization, decreasing firing and inhibiting glutamatergic excitation by both pre- and postsynaptic mechanisms. These results broaden the range of mechanisms controlling motor neuron inhibition by riluzole and are relevant to researchers and clinicians interested in understanding ALS pathogenesis and treatment. PMID: 23741042 [PubMed - indexed for MEDLINE]
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Related Articles Guidelines of the Brazilian society of bone Marrow transplantation on hematopoietic stem cell transplantation as a treatment for the autoimmune diseases systemic sclerosis and multiple sclerosis. Rev Bras Hematol Hemoter. 2013;35(2):134-43 Authors: Rodrigues MC, Hamerschlak N, de Moraes DA, Simões BP, Rodrigues M, Ribeiro AA, Voltarelli JC PMID: 23741192 [PubMed]
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Related Articles Involvement of microRNA in microglia-mediated immune response. Clin Dev Immunol. 2013;2013:186872 Authors: Guedes J, Cardoso AL, Pedroso de Lima MC Abstract MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that play an important role in the regulation of gene expression at the posttranscriptional level. Due to their ability to simultaneously modulate the fate of different genes, these molecules are particularly well suited to act as key regulators during immune cell differentiation and activation, and their dysfunction can contribute to pathological conditions associated with neuroinflammation. Recent studies have addressed the role of miRNAs in the differentiation of progenitor cells into microglia and in the activation process, aiming at clarifying the origin of adult microglia cells and the contribution of the central nervous system (CNS) environment to microglia phenotype, in health and disease. Altered expression of several miRNAs has been associated with Alzheimer's disease, multiple sclerosis, and ischemic injury, hence strongly advocating the use of these small molecules as disease markers and new therapeutic targets. This review summarizes the recent advances in the field of miRNA-mediated regulation of microglia development and activation. We discuss the role of specific miRNAs in the maintenance and switching of microglia activation states and illustrate the potential of this class of nucleic acids both as biomarkers of inflammation and new therapeutic tools for the modulation of microglia behavior in the CNS. PMID: 23762086 [PubMed - indexed for MEDLINE]
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Related Articles Prospective isolation of murine and human bone marrow mesenchymal stem cells based on surface markers. Stem Cells Int. 2013;2013:507301 Authors: Mabuchi Y, Houlihan DD, Akazawa C, Okano H, Matsuzaki Y Abstract Mesenchymal stem cells (MSCs) are currently defined as multipotent stromal cells that undergo sustained in vitro growth and can give rise to cells of multiple mesenchymal lineages, such as adipocytes, chondrocytes, and osteoblasts. The regenerative and immunosuppressive properties of MSCs have led to numerous clinical trials exploring their utility for the treatment of a variety of diseases (e.g., acute graft-versus-host disease, Crohn's disease, multiple sclerosis, osteoarthritis, and cardiovascular diseases including heart failure and myocardial infarction). On the other hand, conventionally cultured MSCs reflect heterogeneous populations that often contain contaminating cells due to the significant variability in isolation methods and the lack of specific MSC markers. This review article focuses on recent developments in the MSC research field, with a special emphasis on the identification of novel surface markers for the in vivo localization and prospective isolation of murine and human MSCs. Furthermore, we discuss the physiological importance of MSC subtypes in vivo with specific reference to data supporting their contribution to HSC niche homeostasis. The isolation of MSCs using selective markers (combination of PDGFR α and Sca-1) is crucial to address the many unanswered questions pertaining to these cells and has the potential to enhance their therapeutic potential enormously. PMID: 23766770 [PubMed]
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Related Articles [Regenerative strategy for autoimmune neurological diseases using neural stem cells]. Nihon Rinsho. 2013 May;71(5):795-800 Authors: Hitoshi S, Shimizu T, Ikenaka K Abstract Autoimmune demyelinating diseases of central nervous system are relatively uncommon in Asian but, when proceeds to chronic state, disabling neurological conditions. Recent advance in developing disease-modifying reagents for chronic stage of multiple sclerosis is not yet satisfactory and new strategies of therapy are waited. Neural stem cells, which exist in the subependyma and the dentate gyrus of hippocampus of the adult mammalian brain, could be utilized to provide myelin-forming oligodendrocytes and restore function. Some drugs, which are used in clinics, exhibit direct effects on adult neural stem cells to enhance their self-renewal capability and survival and to promote oligodendrocyte differentiation. Alternatively, oligodendrocyte precursor cells derived from iPS cells 3an be transplanted to the demyelinating brains, where the cells extensively migrate out to myelinate naked axons. PMID: 23777084 [PubMed - indexed for MEDLINE]
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Related Articles Hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage. J Hum Hypertens. 2014 Feb;28(2):74-9 Authors: Mennuni S, Rubattu S, Pierelli G, Tocci G, Fofi C, Volpe M Abstract Kidney damage represents a frequent event in the course of hypertension, ranging from a benign to a malignant form of nephropathy depending on several factors, that is, individual susceptibility, degree of hypertension, type of etiology and underlying kidney disease. Multiple mechanisms are involved in determination of kidney glomerular, tubular and interstitial injuries in hypertension. The present review article discusses relevant contributory molecular mechanisms underpinning the promotion of hypertensive renal damage, such as the renin-angiotensin-aldosterone system (RAAS), oxidative stress, endothelial dysfunction, and genetic and epigenetic determinants. We highlighted major pathways involved in the progression of inflammation and fibrosis leading to glomerular sclerosis, tubular atrophy and interstitial fibrosis, thus providing a state of the art review of the pathogenetic background useful for a better understanding of current and future therapeutic strategies toward hypertensive nephropathy. An adequate control of high blood pressure, obtained through an appropriate therapeutic intervention, still represents the key strategy to achieve a satisfactory control of renal damage in hypertension. In this regard, we reviewed the impact of currently available antihypertensive pharmacological treatment on kidney damage, with particular regard to RAAS inhibitors. Notably, recent findings underscored the ability of the kidneys to regenerate and to repair tissue injuries through the differentiation of resident embryonic stem cells. Pharmacological modulation of the renal endogenous reparative process (that is, with angiotensin-converting enzyme inhibitors and AT1 angiotensin II receptor blockers), as well as future therapeutic strategies targeted to the renopoietic system, offers interesting perspectives for the management of hypertensive nephropathy. PMID: 23803592 [PubMed - in process]
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Related Articles [Diagnostic value of brain biopsy in a pediatric multiple sclerosis mimicking brain stem glioma]. Nihon Rinsho Meneki Gakkai Kaishi. 2013;36(3):175-9 Authors: Nakazawa Y, Maekawa T, Oana S, Ishiguro A, Ohta S, Terashima H, Kashii H, Kubota M, Tsutsumi Y, Nakazawa A, Morota N, Sakai H Abstract Diagnosis of multiple sclerosis (MS) is difficult when the lesion mimics glioma or cerebral enchephalitis. We report a case of pediatric MS initially suspected as brain stem glioma. An 11-year-old boy developed left foot joint pain followed by progressive symptoms such as left arm and leg weakness, dysarthria, paraplegia, and decreased level of consciousness. He subsequently developed respiratory distress requiring endotracheal intubation and mechanical ventilation. Magnetic resonance imaging showed a mass measuring 2 cm in the medulla oblongata. Although this mass was initially suspected as a glioma, the patient's acutely progressive disease course was not consistent with this diagnosis. Open biopsy revealed inflammation and demyelination, but no malignant cells were detected. He was treated with steroid pulse therapy, which showed dramatic effects. Nine months later, he developed another episode characterized by several neurological symptoms, and the diagnosis of MS was clinically confirmed. Open brain stem biopsy is technically demanding, but this case demonstrates that appropriate neurosurgical evaluation can play an important role in diagnosis by ruling out glioma and confirming MS. PMID: 23812076 [PubMed - indexed for MEDLINE]
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Related Articles Longitudinal positron emission tomography imaging for monitoring myelin repair in the spinal cord. Ann Neurol. 2013 Nov;74(5):688-98 Authors: Wu C, Zhu J, Baeslack J, Zaremba A, Hecker J, Kraso J, Matthews PM, Miller RH, Wang Y Abstract OBJECTIVE: Novel therapeutic interventions aimed at myelin repair are now under development for neuroprotection as well as functional recovery of patients with multiple sclerosis. However, development of myelin repair therapy necessitates a noninvasive approach for measuring changes in myelin content in vivo in a quantitative fashion not yet possible using magnetic resonance imaging. For this reason, we developed a novel positron emission tomography (PET) probe, termed [11C]MeDAS, that is capable of longitudinally imaging central nervous system myelin content. METHODS: The binding properties of [11C]MeDAS for myelin were systematically evaluated by in vitro and in situ fluorescent staining of the spinal cord and the brain, and by in vivo competitive blocking studies. Longitudinal PET studies were conducted in 3 rat models involving acute focal neuroinflammation in the brain, lysophosphatidylcholine (LPC)-induced focal demyelination in the spinal cord, and experimental autoimmune encephalomyelitis (EAE). Image-guided myelin repair therapy was conducted in an LPC rat model using a mesenchymal stem cell-based hepatocyte growth factor (HGF). Biodistribution and acute toxicity studies of [11C]MeDAS were also conducted. RESULTS: MeDAS selectively stains myelin in the spinal cord and brain. Neuroinflammation did not affect [11C]MeDAS uptake in the brain as long as the myelin sheaths remained intact. Longitudinal PET studies in LPC and EAE rat models demonstrate that [11C]MeDAS uptake changes correlate with associated myelin loss in the spinal cord. Furthermore, using [11C]MeDAS-PET, the efficacy of myelin repair therapy with HGF was longitudinally monitored in vivo. INTERPRETATION: [11C]MeDAS-PET is a promising imaging marker for monitoring myelin pathology in vivo, future applications of which in humans should be achievable. PMID: 23818306 [PubMed - indexed for MEDLINE]
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Related Articles Effective combination of human bone marrow mesenchymal stem cells and minocycline in experimental autoimmune encephalomyelitis mice. Stem Cell Res Ther. 2013 Jul 5;4(4):77 Authors: Hou Y, Ryu CH, Park KY, Kim SM, Jeong CH, Jeun SS Abstract INTRODUCTION: Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). Minocycline ameliorates the clinical severity of MS and exhibits antiinflammatory, neuroprotective activities, and good tolerance for long-term use, whereas it is toxic to the CNS. Recently, the immunomodulation and neuroprotection capabilities of human bone marrow mesenchymal stem cells (hBM-MSCs) were shown in experimental autoimmune encephalomyelitis (EAE). In this study, we evaluated whether the combination of hBM-MSCs and a low-dose minocycline could produce beneficial effects in EAE mice. METHODS: The sensitivity of hBM-MSCs to minocycline was determined by an established cell-viability assay. Minocycline-treated hBM-MSCs were also characterized with flow cytometry by using MSC surface markers and analyzed for their multiple differentiation capacities. EAE was induced in C57BL/6 mice by using immunization with MOG35-55. Immunopathology assays were used to detect the inflammatory cells, demyelination, and neuroprotection. Interferon gamma (IFN-γ)/tumor necrosis factor alpha (TNF-α) and interleukin-4 (IL-4)/interleukin-10 (IL-10), the hallmark cytokines that direct Th1 and Th2 development, were detected with enzyme-linked immunosorbent assay (ELISA). terminal dUTP nick-end labeling (TUNEL) staining was performed to elucidate the cell apoptosis in the spinal cords of EAE mice. RESULTS: Minocycline did not affect the viability, surface phenotypes, or differentiation capacity of hBM-MSCs, while minocycline affected the viability of astrocytes at a high dose. In vivo efficacy experiments showed that combined treatment, compared to the use of minocycline or hBM-MSCs alone, resulted in a significant reduction in clinical scores, along with attenuation of inflammation, demyelination, and neurodegeneration. Moreover, the combined treatment with hBM-MSCs and minocycline enhanced the immunomodulatory effects, which suppressed proinflammatory cytokines (IFN-γ, TNF-α) and conversely increased anti-inflammatory cytokines (IL-4, IL-10). In addition, TUNEL staining also demonstrated a significant decrease of the number of apoptotic cells in the combined treatment compared with either treatment alone. CONCLUSIONS: The combination of hBM-MSCs and minocycline provides a novel experimental protocol to enhance the therapeutic effects in MS. PMID: 23826999 [PubMed - as supplied by publisher]
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Related Articles TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation through Rheb-TORC1-S6K but independently of nutritional status or Notch regulation. J Cell Sci. 2013 Sep 1;126(Pt 17):3884-92 Authors: Quan Z, Sun P, Lin G, Xi R Abstract Tubular sclerosis complex gene products TSC1 and TSC2 have evolutionarily conserved roles in cell growth from Drosophila to mammals. Here we reveal important roles for TSC1/2 in regulating intestinal stem cell (ISC) maintenance and differentiation of the enteroendocrine cell lineage in the Drosophila midgut. Loss of either the Tsc1 or Tsc2 gene in ISCs causes rapid ISC loss through TORC1 hyperactivation, because ISCs can be efficiently rescued by mutation of S6k or by rapamycin treatment. In addition, overexpression of Rheb, which triggers TORC1 activation, recapitulates the phenotype caused by TSC1/2 disruption. Genetic studies suggest that TSC1/2 maintains ISCs independently of nutritional status or Notch regulation, probably by inhibiting cell delamination. We show that Tsc1/Tsc2 mutant ISCs can efficiently produce enterocytes but not enteroendocrine cells, and this altered differentiation potential is also caused by hyperactivation of TORC1. Reduced TORC1-S6K signaling by mutation of S6k, however, has no effect on ISC maintenance or cell lineage differentiation. Our studies demonstrate that hyperactivation of TORC1 following the loss of TSC1/2 is detrimental to stem cell maintenance and multiple lineage differentiation in the Drosophila ISC lineage, a mechanism that could be conserved in other stem cell lineages, including that in humans. PMID: 23843608 [PubMed - in process]
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Related Articles The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis. Am J Stem Cells. 2013;2(2):95-107 Authors: Holloman JP, Ho CC, Hukki A, Huntley JL, Gallicano GI Abstract This article examines the current use and future implications of stem cell therapy in treating Multiple Sclerosis (MS). MS is the most common neurological disease in young adults, affecting approximately two million people worldwide. Currently there is no cure for MS. The standard treatment of MS involves disease-modifying drugs, which work to alleviate the symptoms of MS. However, these drugs carry adverse side effects and are ineffective in preventing disease progression in many MS patients. Hematopoietic stem cell transplantation (HSCT) was first used in 1995 to treat patients with severe rapidly progressing MS. The HSCT treatment protocol has evolved into a less intense conditioning regimen that is currently demonstrating efficacy in treating patients with variable disease severity-with best results in early-stage rapidly progressing MS patients with active CNS inflammation. Mesenchymal stem cell therapy (MSCT) is an experimental stem cell therapy currently undergoing clinical trials. Animal models and early clinical trials have shown promise that MSCT might be a low risk treatment to precipitate neuroregeneration and immunomodulation in MS patients. Specifically, neuroprogenitor and placental-derived mesenchymal stem cells offer the best hope for a practical treatment for MS. Stem cell therapy, and perhaps a combinatorial therapeutic approach, holds promise for a better treatment for MS. PMID: 23862098 [PubMed]
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Related Articles Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain. 2013 Sep;136(Pt 9):2888-903 Authors: Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, Carassiti D, Reynolds R, Salvetti M, Calabresi PA, Coles AJ, Battistini L, Martin R, Burt RK, Muraro PA Abstract Autologous haematopoietic stem cell transplantation has been tried as one experimental strategy for the treatment of patients with aggressive multiple sclerosis refractory to other immunotherapies. The procedure is aimed at ablating and repopulating the immune repertoire by sequentially mobilizing and harvesting haematopoietic stem cells, administering an immunosuppressive conditioning regimen, and re-infusing the autologous haematopoietic cell product. 'Non-myeloablative' conditioning regimens to achieve lymphocytic ablation without marrow suppression have been proposed to improve safety and tolerability. One trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and inflammatory stabilization in treated patients with highly active multiple sclerosis. The aim of the present study was to understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action. Peripheral blood was obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and longitudinally followed for 2 years. We examined the phenotype and function of peripheral blood lymphocytes by cell surface or intracellular staining and multi-colour fluorescence activated cell sorting alone or in combination with proliferation assays. During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+ FoxP3+ T cells and CD56(high) natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+ CD57+ cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a CD161(high) proinflammatory CD8+ T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161(high)CD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut mucosa but expressing the central nervous system-homing receptor CCR6. Detection of mucosal-associated invariant T cells in post-mortem multiple sclerosis brain white matter active lesions confirmed their involvement in the disease pathology. Intracellular cytokine staining demonstrated interferon γ and interleukin 17 production and lack of interleukin 10 production, a pro-inflammatory profile. Mucosal-associated invariant T cell frequency did not change in patients treated with interferon β; and was more depleted after autologous haematopoietic stem cell transplantation than in patients who had received high-dose cyclophosphamide (n = 7) or alemtuzumab (n = 21) treatment alone, suggesting an additive or synergistic effect of the conditioning regime components. We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide and alemtuzumab. PMID: 23864273 [PubMed - indexed for MEDLINE]
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Related Articles The secretome of mesenchymal stem cells: potential implications for neuroregeneration. Biochimie. 2013 Dec;95(12):2246-56 Authors: Paul G, Anisimov SV Abstract Mesenchymal stem cells have shown regenerative properties in many tissues. This feature had originally been ascribed to their multipotency and thus their ability to differentiate into tissue-specific cells. However, many researchers consider the secretome of mesenchymal stem cells the most important player in the observed reparative effects of these cells. In this review, we specifically focus on the potential neuroregenerative effect of mesenchymal stem cells, summarize several possible mechanisms of neuroregeneration and list key factors mediating this effect. We illustrate examples of mesenchymal stem cell treatment in central nervous system disorders including stroke, neurodegenerative disorders (such as Parkinson's disease, Huntington's disease, multiple system atrophy and cerebellar ataxia) and inflammatory disease (such as multiple sclerosis). We specifically highlight studies where mesenchymal stem cells have entered clinical trials. PMID: 23871834 [PubMed - in process]
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Related Articles Entrapment syndrome of multiple nerves in graft-versus-host disease. Muscle Nerve. 2014 Jan;49(1):138-42 Authors: Kleiter I, Poeschl P, Kraus PD, Huber E, Schröder J, Schulte-Mattler W, Holler E, Wolff D Abstract INTRODUCTION: Peripheral nerve entrapment syndromes are associated with hereditary neuropathy with liability to pressure palsies and a variety of rheumatic and endocrinological diseases. METHODS: We report a patient with entrapment syndromes of multiple nerves associated with chronic graft-versus-host-disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Nerve ultrasound, histology, and ultrastructural changes were assessed. RESULTS: The 51-year-old man had developed severe deep dermal sclerosis due to chronic GVHD with a progressive polyneuropathy and entrapment syndromes of multiple nerves. Pre-stenotic enlargement was shown by nerve ultrasound. Histology demonstrated fibrosis of the epineurium with scarce infiltration of macrophages. Electron microscopy demonstrated alterations of the myelin sheaths and marked depletion of normal-sized myelinated nerve fibers. CONCLUSIONS: In addition to polyneuropathy, chronic GVHD can be associated with peripheral nerve entrapment syndromes and should be added to the differential diagnosis of compressive neuropathies. PMID: 23893492 [PubMed - indexed for MEDLINE]
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Related Articles Human mesenchymal stem cells upregulate CD1dCD5(+) regulatory B cells in experimental autoimmune encephalomyelitis. Neuroimmunomodulation. 2013;20(5):294-303 Authors: Guo Y, Chan KH, Lai WH, Siu CW, Kwan SC, Tse HF, Wing-Lok Ho P, Wing-Man Ho J Abstract BACKGROUND/AIMS: Multiple sclerosis (MS) causes significant neurological disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. Human bone marrow mesenchymal stem cells (hMSCs) possess anti-inflammatory and immunosuppressive effects. We studied whether hMSCs affect CD1d(high)CD5(+) regulatory B-cell activity in EAE. METHODS: EAE was induced in C57BL/6N mice by immunization with MOG35-55 peptide. hMSCs were injected intravenously into EAE mice on day 3 and day 12 after first immunization. Mice were sacrificed on day 26. Immunohistochemistry of the spinal cord, serum cytokines levels, production of cytokines by cultured splenic cells, and flow cytometry for splenic Th17 and CD1d(high)CD5(+) regulatory B cells were studied. RESULTS: EAE mice with hMSC treatment on day 3 and day 12 had reduced EAE scores from day 14 to day 26 compared to EAE mice without hMSC treatment, and reduced infiltration of inflammatory cells and demyelination in the spinal cord. EAE mice with hMSC treatment on day 3 and day 12 had: (1) lower serum levels of IL-6, TNF-α (p < 0.0005), and IL-17 (p < 0.005 for day 3, p < 0.0005 for day 12); (2) reduced splenic cell production and secretion of IL-6, TNF-α (p < 0.05), and IL-17 (p < 0.05), and increased splenic production of IL-10; (3) reduced splenic Th17 cells (p < 0.05 for day 3, p < 0.005 for day 12), and (4) increased CD1d(high)CD5(+) regulatory B cells (p < 0.005) compared to EAE mice without hMSC treatment. CONCLUSION: hMSC treatment on day 3 and day 12 suppresses EAE severity. The underlying mechanisms involve downregulation of Th17 cells and upregulation of CD1d(high)CD5(+) regulatory B-cell activity. PMID: 23899693 [PubMed - indexed for MEDLINE]
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Related Articles Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination. PLoS One. 2013;8(7):e69795 Authors: Nessler J, Bénardais K, Gudi V, Hoffmann A, Salinas Tejedor L, Janßen S, Prajeeth CK, Baumgärtner W, Kavelaars A, Heijnen CJ, van Velthoven C, Hansmann F, Skripuletz T, Stangel M Abstract For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC) have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS). In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood-brain-barrier is intact and thus cannot provide support for regenerative processes. PMID: 23922802 [PubMed - in process]
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Related Articles Multimodal imaging of subventricular zone neural stem/progenitor cells in the cuprizone mouse model reveals increased neurogenic potential for the olfactory bulb pathway, but no contribution to remyelination of the corpus callosum. Neuroimage. 2014 Feb 1;86:99-110 Authors: Guglielmetti C, Praet J, Rangarajan JR, Vreys R, De Vocht N, Maes F, Verhoye M, Ponsaerts P, Van der Linden A Abstract Multiple sclerosis is a devastating demyelinating disease of the central nervous system (CNS) in which endogenous remyelination, and thus recovery, often fails. Although the cuprizone mouse model allowed elucidation of many molecular factors governing remyelination, currently very little is known about the spatial origin of the oligodendrocyte progenitor cells that initiate remyelination in this model. Therefore, we here investigated in this model whether subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) contribute to remyelination of the splenium following cuprizone-induced demyelination. Experimentally, from the day of in situ NSPC labeling, C57BL/6J mice were fed a 0.2% cuprizone diet during a 4-week period and then left to recover on a normal diet for 8weeks. Two in situ labeling strategies were employed: (i) NSPCs were labeled by intraventricular injection of micron-sized iron oxide particles and then followed up longitudinally by means of magnetic resonance imaging (MRI), and (ii) SVZ NSPCs were transduced with a lentiviral vector encoding the eGFP and Luciferase reporter proteins for longitudinal monitoring by means of in vivo bioluminescence imaging (BLI). In contrast to preceding suggestions, no migration of SVZ NSPC towards the demyelinated splenium was observed using both MRI and BLI, and further validated by histological analysis, thereby demonstrating that SVZ NSPCs are unable to contribute directly to remyelination of the splenium in the cuprizone model. Interestingly, using longitudinal BLI analysis and confirmed by histological analysis, an increased migration of SVZ NSPC-derived neuroblasts towards the olfactory bulb was observed following cuprizone treatment, indicative for a potential link between CNS inflammation and increased neurogenesis. PMID: 23933305 [PubMed - in process]
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Related Articles PGE2 contributes to in vitro MSC-mediated inhibition of non-specific and antigen-specific T cell proliferation in MS patients. Scand J Immunol. 2013 Nov;78(5):455-62 Authors: Zafranskaya M, Nizheharodava D, Yurkevich M, Ivanchik G, Demidchik Y, Kozhukh H, Fedulov A Abstract Current theories of multiple sclerosis (MS) induction and progression place autoreactive T cells in the focus of the pathogenesis. Mesenchymal/stromal stem cells (MSC) have become a promising alternative approach for pathogenic therapy of MS due to their immunomodulatory properties, underlying mechanisms of which are intensive study. The objective of the research was to investigate the contribution of PGE2 to MSC-mediated suppression in patients with MS using in vitro model of mitogen- and myelin-stimulated T cell cocultivation with autologous/allogeneic MSC. We have showed that PGE2 production depends on cell-to-cell contact of MSC and lymphocytes. The antigenic stimulation did not affect PGE2 production following cocultivation of MSC and PBMC, and it is the presence of MSC in cell culture that significantly increases PGE2 production irrespective of antigenic cultivation conditions. Simultaneously, PGE2 synthesis correlated with indexes of MSC-mediated suppression of mitogen- and myelin-stimulated T cell proliferation in patients with MS. No significant differences in PGE2 production by autologous and allogeneic MSC have been established. These results have demonstrated that in patients with MS, PGE2 is one of the possible factors of MSC immunosuppression. The interrelation between PGE2 concentrations and T cell proliferation suppression mediated by MSC may explain one of the immune mechanisms of cell therapy, which is crucial for the further proper use of MSC in MS research and pathogenic treatment. PMID: 23944654 [PubMed - indexed for MEDLINE]
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Related Articles Valproic Acid attenuates disease symptoms and increases endogenous myelin repair by recruiting neural stem cells and oligodendrocyte progenitors in experimental autoimmune encephalomyelitis. Neurodegener Dis. 2014;13(1):45-52 Authors: Pazhoohan S, Satarian L, Asghari AA, Salimi M, Kiani S, Mani AR, Javan M Abstract BACKGROUND: inefficient remyelination of demyelinated plaques in multiple sclerosis (ms) leads to secondary axon degeneration and progressive disability. therapies that potentiate remyelination would be of immense help for managing MS. Objective: Here, we report the effects of valproic acid (VPA) on focal experimental autoimmune encephalomyelitis (fEAE). METHODS: fEAE was induced in Wistar rats by immunizing the animals with guinea pig spinal cord homogenate emulsified in complete Freund's adjuvant and with pertussis toxin (PT) injection into the spinal cord at the level of T8 vertebra on day 18 after immunization. VPA 300 mg/kg was applied for 4 days after or 8 days before PT administration. Behavioral evaluation, histological assessment and immunohistofluorescence assays were used to evaluate the outcomes. RESULTS: VPA administration had no effect on the development of symptoms, but after discontinuing VPA, animals showed faster recovery. Eight days of pretreatment with VPA accelerated the recovery phase of EAE and increased the number of remyelinated axons in the lesion area. VPA pretreatment also increased the recruitment of neural stem cells and oligodendrocyte precursors within the lesion. CONCLUSIONS: Results suggest VPA as a potential therapy for remyelinating the lesions in MS and for faster recovery from disease relapses. The effect of VPA seems to be mediated by endogenous progenitors recruitment. PMID: 23949302 [PubMed - in process]
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Related Articles Mesenchymal stem cell conditioning promotes rat oligodendroglial cell maturation. PLoS One. 2013;8(8):e71814 Authors: Jadasz JJ, Kremer D, Göttle P, Tzekova N, Domke J, Rivera FJ, Adjaye J, Hartung HP, Aigner L, Küry P Abstract Oligodendroglial progenitor/precursor cells (OPCs) represent the main cellular source for the generation of new myelinating oligodendrocytes in the adult central nervous system (CNS). In demyelinating diseases such as multiple sclerosis (MS) myelin repair activities based on recruitment, activation and differentiation of resident OPCs can be observed. However, the overall degree of successful remyelination is limited and the existence of an MS-derived anti-oligodendrogenic milieu prevents OPCs from contributing to myelin repair. It is therefore of considerable interest to understand oligodendroglial homeostasis and maturation processes in order to enable the development of remyelination therapies. Mesenchymal stem cells (MSC) have been shown to exert positive immunomodulatory effects, reduce demyelination, increase neuroprotection and to promote adult neural stem cell differentiation towards the oligodendroglial lineage. We here addressed whether MSC secreted factors can boost the OPC's oligodendrogenic capacity in a myelin non-permissive environment. To this end, we analyzed cellular morphologies, expression and regulation of key factors involved in oligodendroglial fate and maturation of primary rat cells upon incubation with MSC-conditioned medium. This demonstrated that MSC-derived soluble factors promote and accelerate oligodendroglial differentiation, even under astrocytic endorsing conditions. Accelerated maturation resulted in elevated levels of myelin expression, reduced glial fibrillary acidic protein expression and was accompanied by downregulation of prominent inhibitory differentiation factors such as Id2 and Id4. We thus conclude that apart from their suggested application as potential anti-inflammatory and immunomodulatory MS treatment, these cells might also be exploited to support endogenous myelin repair activities. PMID: 23951248 [PubMed - indexed for MEDLINE]
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Related Articles Comparison of in vivo immunomodulatory effects of intravenous and intraperitoneal administration of adipose-tissue mesenchymal stem cells in experimental autoimmune encephalomyelitis (EAE). Int Immunopharmacol. 2013 Nov;17(3):608-16 Authors: Yousefi F, Ebtekar M, Soleimani M, Soudi S, Hashemi SM Abstract Due to their immunomodulatory and anti-inflammatory competence, mesenchymal stem cells (MSCs) have been considered as a suitable candidate for treatment of autoimmune diseases. Earlier studies have shown that treatment with bone marrow-derived MSCs may modulate immune responses and reduce disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we compare the immune regulatory properties of adipose tissue MSCs (AT-MSCs) in two independent routes of injection; namely intraperitoneal (i.p.) and intravenous (i.v.). We investigated the splenic CD4+CD25+FOXP3+ T cell population known as regulatory T cells, by flow cytometry and their brain cell infiltration by hematoxylin-eosin staining in both i.p. and i.v. routes of AT-MSC administration. We also evaluated the inflammatory cytokine profile including IFN-γ and IL-17 and anti-inflammatory cytokines such as IL-4 by ELISA technique in both routes of cell administration. We show that the i.p. route has a more pronounced effect in maintaining the splenic CD4+CD25+FOXP3+ T cell population and increase of IL-4 secretion. We also showed that i.p. injection of cells resulted in lower IFN-γ secretion and reduced cell infiltration in brain more effectively as compared to the i.v. route. The effects of AT-MSCs on down-regulation of splenocyte proliferation, IL-17 secretion and alleviating the severity of clinical scores were similar in i.p. and i.v. routes. Our data show that, due to their immunomodulative and neuroprotective effects, AT-MSCs may be a proper candidate for stem cell based MS therapy. PMID: 23973288 [PubMed - in process]
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Related Articles Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model. Cell Death Dis. 2013;4:e779 Authors: Jaramillo-Merchán J, Jones J, Ivorra JL, Pastor D, Viso-León MC, Armengól JA, Moltó MD, Geijo-Barrientos E, Martínez S Abstract Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain's white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft. PMID: 23990019 [PubMed - indexed for MEDLINE]
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Related Articles Minimally invasive transplantation of iPSC-derived ALDHhiSSCloVLA4+ neural stem cells effectively improves the phenotype of an amyotrophic lateral sclerosis model. Hum Mol Genet. 2014 Jan 15;23(2):342-54 Authors: Nizzardo M, Simone C, Rizzo F, Ruggieri M, Salani S, Riboldi G, Faravelli I, Zanetta C, Bresolin N, Comi GP, Corti S Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the degeneration of motor neurons. Currently, there is no effective therapy for ALS. Stem cell transplantation is a potential therapeutic strategy for ALS, and the reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) represents a novel cell source. In this study, we isolated a specific neural stem cell (NSC) population from human iPSCs based on high aldehyde dehydrogenase activity, low side scatter and integrin VLA4 positivity. We assessed the therapeutic effects of these NSCs on the phenotype of ALS mice after intrathecal or intravenous injections. Transplanted NSCs migrated and engrafted into the central nervous system via both routes of injection. Compared with control ALS, treated ALS mice exhibited improved neuromuscular function and motor unit pathology and significantly increased life span, in particular with the systemic administration of NSCs (15%). These positive effects are linked to multiple mechanisms, including production of neurotrophic factors and reduction of micro- and macrogliosis. NSCs induced a decrease in astrocyte number through the activation of the vanilloid receptor TRPV1. We conclude that minimally invasive injections of iPSC-derived NSCs can exert a therapeutic effect in ALS. This study contributes to advancements in iPSC-mediated approaches for treating ALS and other neurodegenerative diseases. PMID: 24006477 [PubMed - in process]
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Related Articles Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II). Rev Neurol. 2013 Sep 16;57(6):269-81 Authors: Fernandez O, Arnal-Garcia C, Arroyo-Gonzalez R, Brieva L, Calles-Hernandez MC, Casanova-Estruch B, Comabella M, de Las Heras V, Garcia-Merino JA, Hernandez-Perez MA, Izquierdo G, Matas E, Meca-Lallana JE, Mendibe-Bilbao MM, Munoz-Garcia D, Olascoaga J, Oreja-Guevara C, Prieto JM, Ramio-Torrenta L, Rodriguez-Antiguedad A, Saiz A, Tellez N, Villar LM, Tintore M, Grupo Post-Ectrims GP Abstract The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in October 2012 in France have been summarised in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. This review is the result of the meeting, which is being published in three parts. This second part of the Post-ECTRIMS review discusses the biology of recovery and remyelination in multiple sclerosis (MS) as well as the different repair and endogenous and exogenous remyelination strategies currently being evaluated based on the fact that resident microglia and oligodendroglial progenitor cells have been implicated in the remyelination process. This review also discusses the current state and future use of biomarkers in MS and proposes as markers of neurodegeneration the following: T2 lesion volume and brain atrophy using MRI and the loss of the ganglion cell layer as assessed by optical coherence tomography. A greater future utility for double inversion recovery (DIR) sequences is proposed to correlate cognitive impairment with MS impairment, given its higher diagnostic yield in locating and defining cortical lesions. The availability of novel biomarkers in the future requires strict validation. In this context, this paper proposes possible areas of action to improve the current situation and also presents the latest research results in identifying potential candidates with useful diagnostic characteristics, prognostic characteristics, treatment responses, and safety procedures. PMID: 24008938 [PubMed - indexed for MEDLINE]
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Related Articles Age of the donor reduces the ability of human adipose-derived stem cells to alleviate symptoms in the experimental autoimmune encephalomyelitis mouse model. Stem Cells Transl Med. 2013 Oct;2(10):797-807 Authors: Scruggs BA, Semon JA, Zhang X, Zhang S, Bowles AC, Pandey AC, Imhof KM, Kalueff AV, Gimble JM, Bunnell BA Abstract There is a significant clinical need for effective therapies for primary progressive multiple sclerosis, which presents later in life (i.e., older than 50 years) and has symptoms that increase in severity without remission. With autologous mesenchymal stem cell therapy now in the early phases of clinical trials for all forms of multiple sclerosis (MS), it is necessary to determine whether autologous stem cells from older donors have therapeutic effectiveness. In this study, the therapeutic efficacy of human adipose-derived mesenchymal stem cells (ASCs) from older donors was directly compared with that of cells from younger donors for disease prevention. Mice were induced with chronic experimental autoimmune encephalomyelitis (EAE) using the myelin oligodendrocyte glycoprotein35-55 peptide and treated before disease onset with ASCs derived from younger (<35 years) or older (>60 years) donors. ASCs from older donors failed to ameliorate the neurodegeneration associated with EAE, and mice treated with older donor cells had increased central nervous system inflammation, demyelination, and splenocyte proliferation in vitro compared with the mice receiving cells from younger donors. Therefore, the results of this study demonstrated that donor age significantly affects the ability of human ASCs to provide neuroprotection, immunomodulation, and/or remyelination in EAE mice. The age-related therapeutic differences corroborate recent findings that biologic aging occurs in stem cells, and the differences are supported by evidence in this study that older ASCs, compared with younger donor cells, secrete less hepatocyte growth factor and other bioactive molecules when stimulated in vitro. These results highlight the need for evaluation of autologous ASCs derived from older patients when used as therapy for MS. PMID: 24018793 [PubMed - indexed for MEDLINE]
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Related Articles Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014 Feb;141(2):125-39 Authors: Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y Abstract Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases. PMID: 24076269 [PubMed - in process]
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Related Articles Cell-based reparative therapies for multiple sclerosis. Curr Neurol Neurosci Rep. 2013 Nov;13(11):397 Authors: Ben-Hur T, Fainstein N, Nishri Y Abstract The strong rationale for cell-based therapy in multiple sclerosis is based on the ability of stem and precursor cells of neural and mesenchymal origin to attenuate neuroinflammation, to facilitate endogenous repair processes, and to participate directly in remyelination, if directed towards a myelin-forming fate. However, there are still major gaps in knowledge regarding induction of repair in chronic multiple sclerosis lesions, and whether transplanted cells can overcome the multiple environmental inhibitory factors which underlie the failure of endogenous repair. Major challenges in clinical translation include the determination of the optimal cellular platform, the route of cell delivery, and candidate patients for treatment. PMID: 24078453 [PubMed - in process]
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Related Articles Cell therapy for multiple sclerosis: an evolving concept with implications for other neurodegenerative diseases. Lancet. 2013 Oct 5;382(9899):1204-13 Authors: Rice CM, Kemp K, Wilkins A, Scolding NJ Abstract Multiple sclerosis is a major cause of neurological disability, and particularly occurs in young adults. It is characterised by conspicuous patches of damage throughout the brain and spinal cord, with loss of myelin and myelinating cells (oligodendrocytes), and damage to neurons and axons. Multiple sclerosis is incurable, but stem-cell therapy might offer valuable therapeutic potential. Efforts to develop stem-cell therapies for multiple sclerosis have been conventionally built on the principle of direct implantation of cells to replace oligodendrocytes, and therefore to regenerate myelin. Recent progress in understanding of disease processes in multiple sclerosis include observations that spontaneous myelin repair is far more widespread and successful than was previously believed, that loss of axons and neurons is more closely associated with progressive disability than is myelin loss, and that damage occurs diffusely throughout the CNS in grey and white matter, not just in discrete, isolated patches or lesions. These findings have introduced new and serious challenges that stem-cell therapy needs to overcome; the practical challenges to achieve cell replacement alone are difficult enough, but, to be useful, cell therapy for multiple sclerosis must achieve substantially more than the replacement of lost oligodendrocytes. However, parallel advances in understanding of the reparative properties of stem cells--including their distinct immunomodulatory and neuroprotective properties, interactions with resident or tissue-based stem cells, cell fusion, and neurotrophin elaboration--offer renewed hope for development of cell-based therapies. Additionally, these advances suggest avenues for translation of this approach not only for multiple sclerosis, but also for other common neurological and neurodegenerative diseases. PMID: 24095194 [PubMed - indexed for MEDLINE]
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Related Articles A regenerative approach to the treatment of multiple sclerosis. Nature. 2013 Oct 17;502(7471):327-32 Authors: Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL Abstract Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches. PMID: 24107995 [PubMed - indexed for MEDLINE]
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Related Articles Can we switch microglia's phenotype to foster neuroprotection? Focus on multiple sclerosis. Immunology. 2014 Mar;141(3):328-39 Authors: Giunti D, Parodi B, Cordano C, Uccelli A, Kerlero de Rosbo N Abstract Microglia cells, the resident innate immune cells in the brain, are highly active, extending and retracting highly motile processes through which they continuously survey their microenvironment for 'danger signals' and interact dynamically with surrounding cells. Upon sensing changes in their central nervous system microenvironment, microglia become activated, undergoing morphological and functional changes. Microglia activation is not an 'all-or-none' process, but rather a continuum depending on encountered stimuli, which is expressed through a spectrum of molecular and functional phenotypes ranging from so-called 'classically activated', with a highly pro-inflammatory profile, to 'alternatively activated' associated with a beneficial, less inflammatory, neuroprotective profile. Microglia activation has been demonstrated in most neurological diseases of diverse aetiology and has been implicated as a contributor to neurodegeneration. The possibility to promote microglia's neuroprotective phenotype has therefore become a therapeutic goal. We have focused our discussion on the role of microglia in multiple sclerosis, a prototype of inflammatory, demyelinating, neurodegenerative disease, and on the effect of currently approved or on-trial anti-inflammatory therapeutic strategies that might mediate neuroprotection at least in part through their effect on microglia by modifying their behaviour via a switch of their functional phenotype from a detrimental to a protective one. In addition to pharmaceutical approaches, such as treatment with glatiramer acetate, interferon-β, fingolimod or dimethyl fumarate, we address the alternative therapeutic approach of treatment with mesenchymal stem cells and their potential role in neuroprotection through their 'calming' effect on microglia. PMID: 24116890 [PubMed - in process]
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Related Articles T cells from autoimmune patients display reduced sensitivity to immunoregulation by mesenchymal stem cells: role of IL-2. Autoimmun Rev. 2014 Feb;13(2):187-96 Authors: Ben-Ami E, Miller A, Berrih-Aknin S Abstract Mesenchymal stem cells (MSCs) are multipotent progenitor cells which have been shown to possess broad immunoregulatory and anti-inflammatory capabilities, making them a promising tool to treat autoimmune diseases (AIDs). Nevertheless, as in recent years T cells from AID patients have been found to resist suppression by regulatory T cells, the question of whether they could be regulated by MSCs arises. To use MSCs as a therapeutic tool in human autoimmune diseases, one prerequisite is that T cells from autoimmune patients will be sensitive to these stem cells. The aim of this work was to investigate the ability of healthy donor derived MSCs to inhibit the proliferation of T cells from two pathophysiologically different AIDs: Multiple Sclerosis (MS) and Myasthenia Gravis (MG). We show that MSC-induced inhibition of interferon-γ production and surface expression of the CD3, CD4 and CD28 receptors by activated lymphocytes was similar in the AID patients and healthy controls. Contrarily, the MSCs' ability to suppress the proliferation of T cells of both diseases was significantly weaker compared to their ability to affect T cells of healthy individuals. Although we found that the inhibitory mechanism is mediated through CD14+ monocytes, the faulty cellular component is the patients' T cells. MSC-treated MS and MG lymphocytes were shown to produce significantly more IL-2 than healthy subjects while coupling of the MSC treatment with neutralizing IL-2 antibodies resulted in inhibition levels similar to those of the healthy controls. MSCs were also found to down-regulate the lymphocyte surface expression of the IL-2 receptor (CD25) through both transcription inhibition and induction of receptor shedding. Addition of IL-2 to MSC-inhibited lymphocytes restored proliferation thus suggesting a key role played by this cytokine in the inhibitory mechanism. Taken together, these results demonstrate the potential of a MSC-based cellular therapy for MS, MG and possibly other autoimmune diseases but also highlight the need for a better understanding of the underlying mechanisms for development and optimization of clinical protocols. PMID: 24121085 [PubMed - indexed for MEDLINE]
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Related Articles Mobilization of progenitors in the subventricular zone to undergo oligodendrogenesis in the Theiler's virus model of multiple sclerosis: implications for remyelination at lesions sites. Exp Neurol. 2013 Dec;250:348-52 Authors: Mecha M, Feliú A, Carrillo-Salinas FJ, Mestre L, Guaza C Abstract Remyelination involves the generation of new myelin sheaths around axons, as occurs spontaneously in many multiple sclerosis (MS) lesions and other demyelinating diseases. When considering repairing a diseased brain, the adult mouse subventricular zone (SVZ) is of particular interest since the stem cells in this area can migrate and differentiate into the three major cell types in the central nervous system (CNS). In Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), we assessed the relative contribution of the SVZ to the remyelination in the corpus callosum at preclinical stages in this MS model. CNPase, MBP and Luxol Fast Blue staining revealed prominent demyelination 35days post-infection (dpi), concomitant with a strong staining in GFAP(+) type B astrocytes in the SVZ and the increased proliferation in this area. The migration of oligodendrocyte progenitors from the SVZ contributed to the remyelination observed at 60 dpi, evident through the number of APC(+)/BrdU(+) mature oligodendrocytes in the corpus callosum of infected animals. These data suggest that the inflammation induced by the Theiler's virus not only provokes strong preclinical demyelination but also, it is correlated with oligodendrocyte generation in the adult SVZ, cells that along with resident progenitor cells contribute to the prompt remyelination observed in the corpus callosum. PMID: 24148569 [PubMed - indexed for MEDLINE]
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Related Articles Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo. J Neuroimmunol. 2013 Dec 15;265(1-2):51-60 Authors: Natarajan C, Yao SY, Zhang F, Sriram S Abstract We examined the activation of innate immune pathway mediated by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in oligodendrocyte precursor cells (OPCs). We show that activation of NOD2 by ligand peptidoglycan (PGN) leads to the recruitment and phosphorylation of receptor-interacting serine/threonine kinase 2 (RIPK2). Phosphorylation of RIPK2 is followed by phosphorylation of neuronal nitric oxide synthase (nNOS), increase in NOS activity and subsequent accumulation of nitric oxide (NO) mediated N-tyrosinylated compounds in OPCs. The reversal of NOS activity by the nNOS inhibitor 7-nitroindazole (7-NI), but not by the iNOS inhibitor L-canavanine, supported the conclusion that the increased NOS activity was due to the selective activation of nNOS in OPCs. In addition, NO mediated injury to OPC was reflected in reduction in activity of respiratory enzymes such as complex I and IV, decrease in mitochondrial membrane potential and release of cytochrome-C from mitochondria. Furthermore, intracerebral injection of PGN into corpus callosum (CC) of rats led to the development of demyelination, which appeared as early as by day 3 post-injection, and involved the trunk of the CC by day 14. Accumulation of N-tyrosinylated proteins was seen in oligodendrocytes in regions of the CC which were in close proximity to the injection site. Taken together, these results suggest that PGN induced formation of NO, mitochondrial dysfunction and accumulation of N-tyrosinylated proteins in oligodendrocytes are likely mediators of central nervous system demyelination. PMID: 24169446 [PubMed - indexed for MEDLINE]
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Related Articles Cognitive fatigue in individuals with multiple sclerosis undergoing immunoablative therapy and hematopoietic stem cell transplantation. J Neurol Sci. 2014 Jan 15;336(1-2):132-7 Authors: Berard JA, Bowman M, Atkins HL, Freedman MS, Walker LA Abstract BACKGROUND: Fatigue presents as a significant problem in multiple sclerosis (MS). Cognitive fatigue (CF) can be defined as a decrease in, or inability to maintain task performance throughout the duration of a continuous cognitive task. CF was evaluated using the Paced Auditory Serial Addition Test (PASAT) both pre- and post-immunoablation and hematopoietic stem cell transplantation (IA-HSCT) over a 3-year follow-up period. The magnitude of CF was examined and the impact of scoring methodology was evaluated. METHODS: Twenty-three individuals with rapidly progressive MS and poor prognosis underwent high dose immunosuppression and subsequent HSCT. Individuals completed the 3″ and 2″ PASAT at baseline and every 6 months thereafter over a period of 36 months. As scoring methodology can impact its sensitivity to CF, the PASAT was scored according to three scoring methods. RESULTS: CF was noted across all three scoring methods at baseline and at the majority of time points post-IA-HSCT on both the 3″ and 2″ PASAT. The magnitude of CF remained consistent both pre-and post-IA-HSCT. CONCLUSIONS: While results suggest that the procedure itself does not ameliorate an individual's susceptibility to CF; neither does it seem to negatively impact levels of CF. As such, results support the notion that the IA-HSCT procedure, despite its aggressive nature, does not exacerbate CF in this particular sample. PMID: 24189209 [PubMed - in process]
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Related Articles Hepatocyte growth factor regulates immune reactions caused by transplantation and autoimmune diseases. Yakugaku Zasshi. 2013;133(11):1159-67 Authors: Iwasaki T, Shibasaki S Abstract Hepatocyte growth factor (HGF) was first identified and cloned as a mitogenic protein for hepatocytes, and subsequent studies revealed that HGF has multiple biological effects on a wide variety of cells, including mitogenic, motogenic, morphogenic, anti-apoptotic, and angiogenic activities. It plays roles in organizing tissues during development and regeneration. HGF may be applied for the treatment of acute onset diseases such as fulminant hepatitis, myocardial infarction, acute renal failure, cerebral infarction, and chronic diseases like liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, and arteriosclerosis obliterans. HGF also has immunomodulatory activities and we previously demonstrated that its administration inhibited acute graft-versus-host disease (GVHD) after treatment with hematopoietic stem cell transplantation. We also demonstrated that HGF inhibited lupus nephritis induced by chronic GVHD and dermal sclerosis in systemic sclerosis using model mice. More than 7 hundred thousand patients suffer from rheumatoid arthritis (RA) in Japan. Although the prognosis of these patients has improved by the treatment of biological agents such as TNF-α and IL-6 blockers, there remain many for whom these agents have not proved beneficial. Recently, using RA model mice, we demonstrated that the HGF antagonist, NK4, can block disease progression of RA through its anti-angiogenic and immunomodulatory actions. In this review article, we discuss the possible roles of HGF signaling for the treatment of immunological reactions in transplantation and autoimmune diseases. PMID: 24189557 [PubMed - in process]
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Related Articles Transplantation of umbilical cord and bone marrow-derived mesenchymal stem cells in a patient with relapsing-remitting multiple sclerosis. Cell Adh Migr. 2013 Sep-Oct;7(5):404-7 Authors: Hou ZL, Liu Y, Mao XH, Wei CY, Meng MY, Liu YH, Zhuyun Yang Z, Zhu H, Short M, Bernard C, Xiao ZC Abstract There is currently great interest in the use of mesenchymal stem cells as a therapy for multiple sclerosis with potential to both ameliorate inflammatory processes as well as improve regeneration and repair. Although most clinical studies have used autologous bone marrow-derived mesenchymal stem cells, other sources such as allogeneic umbilical cord-derived cells may provide a more accessible and practical supply of cells for transplantation. In this case report we present the treatment of aggressive multiple sclerosis with multiple allogenic human umbilical cord-derived mesenchymal stem cell and autologous bone marrow-derived mesenchymal stem cells over a 4 y period. The treatments were tolerated well with no significant adverse events. Clinical and radiological disease appeared to be suppressed following the treatments and support the expansion of mesenchymal stem cell transplantation into clinical trials as a potential novel therapy for patients with aggressive multiple sclerosis. PMID: 24192520 [PubMed - in process]
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Related Articles Multiple Sclerosis International Federation: stimulating international cooperation in research. Neurology. 2013 Nov 12;81(20):1793-5 Authors: Thompson AJ, Chandraratna D Abstract The MS International Federation (MSIF), established in 1967, links the activities of over 85 national multiple sclerosis (MS) societies worldwide. Over those 45 years, and particularly in the last 20, it has seen dramatic changes in our understanding, treatment, and multidisciplinary management of people with MS. However, these advances are not universal and there are embarrassing discrepancies in the levels of treatment and care provided in different parts of the world. MSIF's research strategy is guided by an International Medical and Scientific Board composed of 70 experts in MS, nominated by our member organizations and incorporating an Executive Committee. Our strategy focuses on areas that might benefit from a global approach, those that are newly emerging, and those that are particularly challenging. We encourage young investigators to enter the field of MS research, and particularly support those from underdeveloped countries to facilitate transfer of knowledge and expertise from more "expert" areas. Our current portfolio focuses on progressive MS, pediatric MS, and stem cell therapy. PMID: 24218313 [PubMed - indexed for MEDLINE]
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Related Articles Neurotrophin 3 transduction augments remyelinating and immunomodulatory capacity of neural stem cells. Mol Ther. 2014 Feb;22(2):440-50 Authors: Yang J, Yan Y, Xia Y, Kang T, Li X, Ciric B, Xu H, Rostami A, Zhang GX Abstract Neural stem cells (NSCs) have therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, to date, their use has resulted in only limited clinical and pathological improvement. To enhance their therapeutic capacity, in the present study, we transduced bone marrow-derived NSCs (BM-NSCs) with neurotrophin 3 (NT-3), a potent neurotrophic factor that is both neuroprotective and immunomodulatory. We found that BM-NSCs transduced with NT-3 reduced central nervous system (CNS) inflammation and neurological deficits in ongoing EAE significantly more than conventional NSC therapy, and, in addition, had the following advantages: (i) enhanced BM-NSC proliferation and differentiation into oligodendrocytes and neurons, as well as inhibited differentiation into astrocytes, thus promoting remyelination and neuronal repopulation, and reducing astrogliosis; (ii) enhanced anti-inflammatory capacity of BM-NSCs, thus more effectively suppressing CNS inflammation and accelerating remyelination; (iii) the easy accessibility of BM-NSCs provides another advantage over brain-derived NSCs for MS therapy; and (iv) a novel Tet-on system we used enables efficient control of NT-3 expression. Thus, our study provides a novel approach to break the vicious inflammation-demyelination cycle, and could pave the way to an easily accessible and highly effective therapy for CNS inflammatory demyelination. PMID: 24247929 [PubMed - in process]
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Related Articles The molecular study of IFNβ pleiotropic roles in MS treatment. Iran J Neurol. 2013;12(4):149-156 Authors: Kay M, Hojati Z, Dehghanian F Abstract Multiple sclerosis (MS) is one of the most important autoimmune diseases recognized by demyelination and axonal lesion. It is the most common cause of disability in the young population. Various immunomodulatory and immunosuppressive therapies, including different formulations of interferon beta (IFNβ), glatiramer acetate (GA), mitoxantrone, and natalizumab are available for this disease. However, interferon has been the best prescribed. Although the precise mechanism of IFNβ is unclear, many studies indicate some potential mechanism including blocking T cells activation, controlling pro- and anti-inflammatory cytokine secretion, preventing activated immune cell migration through BBB, and inducing repair activity of damaged nerve cells by differentiating neural stem cells into oligodendrocytes. These molecular mechanisms have significant roles in IFNβ therapy. More researches are required in order for us to comprehend the mechanism of action of IFNβ, and improve and develop drugs for more efficient MS treatment. PMID: 24250925 [PubMed - as supplied by publisher]
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Related Articles Bone marrow mesenchymal stromal cells isolated from multiple sclerosis patients have distinct gene expression profile and decreased suppressive function compared with healthy counterparts. Cell Transplant. 2013 Nov 20; Authors: de Oliveira GL, de Lima KW, Colombini AM, Pinheiro DG, Panepucci RA, Palma PV, Brum DG, Covas DT, Simões BP, de Oliveira MC, Donadi EA, Malmegrim KC Abstract Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system, due to immune reaction against myelin proteins. Multipotent mesenchymal stromal cells (MSCs) present immunosuppressive effects and have been used for the treatment of autoimmune diseases. In our study, gene expression profile and in vitro immunomodulatory function tests were used to compare bone marrow?derived MSCs obtained from MS patients, at pre? and post?autologous hematopoietic stem cell transplantation (AHSCT), with those from healthy donors. Patient MSCs comparatively exhibited: i) senescence in culture, ii) similar osteogenic and adipogenic differentiation potential, iii) decreased expression of CD105, CD73, CD44 and HLA?A/B/C molecules, iv) distinct transcription profile at pre?AHSCT compared with control MSCs, yielding 618 differentially expressed genes, including the downregulation of TGFB1 and HGF genes and modulation of the FGF and HGF signaling pathways, v) reduced antiproliferative effect when pre?AHSCT MSCs were cocultured with allogeneic T?lymphocytes, vi) decreased secretion of IL?10 and TGF?β in supernatants of both cocultures (pre? and post?AHSCT MSCs), vii) similar percentages of regulatory cells recovered after MSC cocultures. The transcriptional profile of patient MSCs isolated six months post?transplantation was closer to pre?AHSCT samples than from healthy MSCs. Considering that patient MSCs exhibited phenotypic changes, distinct transcriptional profile and functional defects implicated in MSC immunomodulatory and immunosuppressive activity, we suggest that further MS clinical studies should be conducted using allogeneic bone marrow MSCs derived from healthy donors. We also demonstrated that treatment of MS patients with AHSCT does not reverse the transcriptional and functional alterations observed in patient MSCs. PMID: 24256874 [PubMed - as supplied by publisher]
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Related Articles RECENT ADVANCES IN MESENCHYMAL STEM CELL IMMUNOMODULATION. THE ROLE OF MICROVESICLES. Cell Transplant. 2013 Nov 21; Authors: Fierabracci A, Del Fattore A, Luciano R, Muraca M, Teti A, Muraca M Abstract Mesenchymal stem cells are the most widely used cell phenotype for therapeutic applications, the main reasons being their well-established abilities to promote regeneration of injured tissues and to modulate immune responses. Efficacy was reported in the treatment of several animal models of inflammatory and autoimmune diseases and, in clinical settings, for the management of disorders such as GVHD, Systemic Lupus Erythematosus, multiple sclerosis and inflammatory bowel disease. The effects of mesenchymal stem cells are believed to be largely mediated by paracrine signals, and several secreted molecules have been identified as contributors to the net biological effect. Recently, it has been recognized that bioactive molecules can be shuttled from cell to cell packed in microvesicles, tiny portions of cytoplasm surrounded by a membrane. Coding and non-coding RNAs are also carried in such microvesicles, transferring relevant biological activity to target cells. Several reports indicate that the regenerative effect of mesenchymal stem cells can be reproduced by microvesicles isolated from their culture medium. More recent evidence suggests that the immunomodulatory effects of mesenchymal stem cells are also at least partially mediated by secreted microvesicles. These findings allow better understanding of the mechanisms involved in cell-to-cell interaction and may have interesting implications for the development of novel therapeutic tools in place of the parent cells. PMID: 24268069 [PubMed - as supplied by publisher]
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Related Articles IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. J Neuroimmunol. 2014 Jan 15;266(1-2):12-23 Authors: Pusic AD, Pusic KM, Clayton BL, Kraig RP Abstract Dendritic cells (DCs) release exosomes with different characteristics based on stimulus. Here, we showed that DC cultures stimulated with low-level IFNγ released exosomes (IFNγ-DC-Exos) that contained microRNA species that can increase baseline myelination, reduce oxidative stress, and improve remyelination following acute lysolecithin-induced demyelination. Furthermore, nasally administered IFNγ-DC-Exos increased CNS myelination in vivo. IFNγ-DC-Exos were preferentially taken up by oligodendrocytes, suggesting that they directly impact oligodendrocytes to increase myelination. Thus, our results show great potential for use of these IFNγ-DC-Exos as a therapeutic to promote remyelination in multiple sclerosis and dysmyelinating syndromes. PMID: 24275061 [PubMed - indexed for MEDLINE]
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Related Articles Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments. Adv Drug Deliv Rev. 2013 Dec 2; Authors: McGivern JV, Ebert AD Abstract In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds. PMID: 24309014 [PubMed - as supplied by publisher]
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Related Articles Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia. 2014 Feb;62(2):284-99 Authors: Pusic AD, Kraig RP Abstract Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression. However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells-both under control conditions and after acute demyelination. Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination. PMID: 24339157 [PubMed - in process]
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Related Articles Evaluation of Lovastatin Effects on Expression of Anti-apoptotic Nrf2 and PGC-1α Genes in Neural Stem Cells Treated with Hydrogen Peroxide. Mol Neurobiol. 2014 Jan 5; Authors: Abdanipour A, Tiraihi T, Noori-Zadeh A, Majdi A, Gosaili R Abstract Reactive oxygen species and oxidative stress are associated with various cell processes, including cell survival and apoptosis. Oxidative stress has been implicated in the pathogenesis of several neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). In the present study, we evaluated the effects of lovastatin chemoprotection against hydrogen peroxide-induced oxidative stress in bone marrow stromal cell-derived neural stem cells (BMSC-derived NSCs) and whether it has protective effects. BMSC-derived NSCs were pretreated with different doses of lovastatin for 48 h and then exposed to 125 μM H2O2 for 30 min. Using MTT, TUNEL assay, and real-time RT-PCR, we evaluated the effects of lovastatin on cell survival, apoptosis, and PGC-1α and Nrf2 expression rates in pretreated BMSC-derived NSCs compared to control groups. Results showed that apoptosis rate in the lovastatin-pretreated BMSC-derived NSCs was significantly decreased compared to the control group. Our findings suggest that lovastatin protects NSCs against oxidative stress-induced cell death, and therefore, it may be used to promote the survival rate of NSCs and can be a candidate for treatment of oxidative stress-mediated neurological diseases. PMID: 24390568 [PubMed - as supplied by publisher]
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Related Articles Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression. EMBO Mol Med. 2014 Mar;6(3):322-34 Authors: Chen C, Akiyama K, Yamaza T, You YO, Xu X, Li B, Zhao Y, Shi S Abstract Bone marrow mesenchymal stem cells (BMMSCs) are capable of differentiating into multiple cell types and regulating immune cell response. However, the mechanisms that govern the immunomodulatory properties of BMMSCs are still not fully elucidated. Here we show that telomerase-deficient BMMSCs lose their capacity to inhibit T cells and ameliorate the disease phenotype in systemic sclerosis mice. Restoration of telomerase activity by telomerase reverse transcriptase (TERT) transfection in TERT(-/-) BMMSCs rescues their immunomodulatory functions. Mechanistically, we reveal that TERT, combined with β-catenin and BRG1, serves as a transcriptional complex, which binds the FAS ligand (FASL) promoter to upregulate FASL expression, leading to an elevated immunomodulatory function. To test the translational value of these findings in the context of potential clinical therapy, we used aspirin treatment to upregulate telomerase activity in BMMSCs, and found a significant improvement in the immunomodulatory capacity of BMMSCs. Taken together, these findings identify a previously unrecognized role of TERT in improving the immunomodulatory capacity of BMMSCs, suggesting that aspirin treatment is a practical approach to significantly reduce cell dosage in BMMSC-based immunotherapies. PMID: 24401839 [PubMed - in process]
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Related Articles Beneficial actions of the anti-inflammatory dimethyl fumarate in glioblastomas. Surg Neurol Int. 2013;4:160 Authors: Ghods AJ, Glick R, Braun D, Feinstein D Abstract BACKGROUND: Dimethylfumarate (DMF), a drug used in the treatment of psoriasis and multiple sclerosis, has been shown to limit the growth of melanoma cells. The ability of DMF to inhibit the Rel protein has been used to explain the antioncogenic properties of this drug. Studies analyzing the effect of DMF in gliomas are limited. Therefore, we investigated the potential antitumor effects of DMF by assessing its effects on proliferation, cell death, and differentiation in gliomas in several glioma models. METHODS: Mouse glioma Gl261, human glioblastoma A172 and human glioblastoma cells from patients were exposed to DMF at therapeutic concentrations (100 μM) and supratherapeutic concentrations (300 μM) and studies to assess proliferation, cellular lysis, and differentiation undertaken. The 5-bromo-2'-deoxyuridine (BRDU) proliferation assay and lactate dehydrogenase LDH cell lysis assay were used. Immunocytochemistry was used to assess differentiation: CD133 (stem cell marker), Nestin (progenitor marker), Sox2 (progenitor marker), β-tubulin III (neuronal marker), glial fibrillary acidic protein (astrocytic marker), and myelin basic protein (oligodendrocytic marker). We also assessed cellular expression of nuclear factor kappa B (NF-κB) via immunocytochemistry. RESULTS: Proliferation significantly decreased and tumor cell lysis significantly increased in all tumor cell lines after exposure to DMF. The human glioblastoma cells expressed the Neuronal Stem Cell marker CD133, Progenitor Cell markers, Neuronal and Astrocytic Cell Markers in vitro. When exposed to DMF, a drastic decline in CD133 expression was observed in addition to a decrease in the expression of NF-κB. CONCLUSION: DMF appears to have a promising role in the treatment of malignant brain neoplasms. DMF reduced proliferation rate, generated cell lysis, decreased the expression of NF-κB, and restricted the growth of CD133 cells in gliomas. This suggests that DMF may be considered for further antitumor studies, and provide a new treatment modality for brain tumors. PMID: 24404403 [PubMed]
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Related Articles Comparison of human adult stem cells from adipose tissue and bone marrow in the treatment of experimental autoimmune encephalomyelitis. Stem Cell Res Ther. 2014 Jan 9;5(1):2 Authors: Semon JA, Maness C, Zhang X, Sharkey SA, Beuttler MM, Shah FS, Pandey AC, Gimble JM, Zhang S, Scruggs BA, Strong AL, Strong TA, Bunnell BA Abstract INTRODUCTION: While administration of ex vivo culture-expanded stem cells has been used to study immunosuppressive mechanisms in multiple models of autoimmune diseases, less is known about the uncultured, nonexpanded stromal vascular fraction (SVF)-based therapy. The SVF is composed of a heterogeneous population of cells and has been used clinically to treat acute and chronic diseases, alleviating symptoms in a range of tissues and organs. METHODS: In this study, the ability of human SVF cells was compared with culture-expanded adipose stem cells (ASCs) and bone-derived marrow stromal cells (BMSCs) as a treatment of myelin oligodendrocyte glycoprotein (35-55)-induced experimental autoimmune encephalitis in C57Bl/6J mice, a well-studied multiple sclerosis model (MS). A total of 1 × 106 BMSCs, ASCs, or SVF cells were administered intraperitoneally concomitantly with the induction of disease. Mice were monitored daily for clinical signs of disease by three independent, blinded investigators and rated on a scale of 0 to 5. Spinal cords were obtained after euthanasia at day 30 and processed for histological staining using luxol fast blue, toluidine blue, and hematoxylin and eosin to measure myelin and infiltrating immune cells. Blood was collected from mice at day 30 and analyzed by enzyme-linked immunosorbent assay to measure serum levels of inflammatory cytokines. RESULTS: The data indicate that intraperitoneal administration of all cell types significantly ameliorates the severity of disease. Furthermore, the data also demonstrate, for the first time, that the SVF was as effective as the more commonly cultured BMSCs and ASCs in an MS model. All cell therapies also demonstrated a similar reduction in tissue damage, inflammatory infiltrates, and sera levels of IFNγ and IL-12. While IFNγ levels were reduced to comparable levels between treatment groups, levels of IL-12 were significantly lower in SVF-treated than BMSC-treated or ASC-treated mice. CONCLUSIONS: Based on these data, it is evident that SVF cells have relevant therapeutic potential in an animal model of chronic MS and might represent a valuable tool for stem cell-based therapy in chronic inflammatory disease of the central nervous system. SVF offers advantages of direct and rapid isolation procedure in a xenobiotic-free environment. PMID: 24405805 [PubMed - as supplied by publisher]
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Related Articles T cell mediated suppression of neurotropic coronavirus replication in neural precursor cells. Virology. 2014 Jan 20;449:235-43 Authors: Plaisted WC, Weinger JG, Walsh CM, Lane TE Abstract Neural precursor cells (NPCs) are the subject of intense investigation for their potential to treat neurodegenerative disorders, yet the consequences of neuroinvasive virus infection of NPCs remain unclear. This study demonstrates that NPCs support replication following infection by the neurotropic JHM strain of mouse hepatitis virus (JHMV). JHMV infection leads to increased cell death and dampens IFN-γ-induced MHC class II expression. Importantly, cytokines secreted by CD4+ T cells inhibit JHMV replication in NPCs, and CD8+ T cells specifically target viral peptide-pulsed NPCs for lysis. Furthermore, treatment with IFN-γ inhibits JHMV replication in a dose-dependent manner. Together, these findings suggest that T cells play a critical role in controlling replication of a neurotropic virus in NPCs, a finding which has important implications when considering immune modulation for NPC-based therapies for treatment of human neurologic diseases. PMID: 24418558 [PubMed - indexed for MEDLINE]
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Related Articles Osthole augments therapeutic efficiency of neural stem cells-based therapy in experimental autoimmune encephalomyelitis. J Pharmacol Sci. 2014;124(1):54-65 Authors: Gao Z, Wen Q, Xia Y, Yang J, Gao P, Zhang N, Li H, Zou S Abstract The therapeutic potential of adult neural stem cells (NSCs)-derived from bone marrow (BM) has been recently described in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis; however, the beneficial effects are modest due to their marginal anti-inflammatory capacity. To overcome this weakness and endow BM-NSC therapy with profound anti-inflammatory capacity, in this study we pretreated EAE mice with osthole, a natural coumarin with a broad spectrum of pharmacological activities, including anti-inflammation, immunomodulation, and neuroprotection, before NSC-application and continued throughout the study. We found that osthole conferred a potent anti-inflammatory capacity to this BM-NSC therapy, thus more profoundly suppressing ongoing EA and exhibiting significant advantages over conventional NSC-therapy as follows: 1) Enhanced anti-inflammatory effect, thus improving survival environment for engrafted BM-NSCs and protecting myelin sheaths from further demyelination; 2)Drove transplanted (exogenous) BM-NSCs to differentiate into more oligodendrocytes and neurons but inhibited differentiation into astrocytes, thus promoting remyelination and axonal growth, and reducing astrogliosis; and 3) augmented CNS neurotrophic support thus promoted resident (endogenous) repair of myelin/axonal damage. These effects make the BM-NSCs-based therapy a more promising approach to enhance remyelination and neuronal repopulation, thus more effectively promoting anatomic and functional recovery from neurological deficits. PMID: 24441773 [PubMed - in process]
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Related Articles Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model. PLoS One. 2014 Jan 21;9(1):e85007 Authors: Zhang X, Bowles AC, Semon JA, Scruggs BA, Zhang S, Strong AL, Gimble JM, Bunnell BA Abstract Multiple sclerosis (MS), characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs) for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE), a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression. PMID: 24465465 [PubMed - in process]
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Related Articles Integrin/Chemokine Receptor Interactions in the Pathogenesis of Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol. 2014 Jan 30; Authors: Banisadr G, Schwartz SR, Podojil JR, Piccinini LA, Lanker S, Miller SD, Miller RJ Abstract Excessive infiltration of leukocytes and the elaboration of inflammatory cytokines are believed to be responsible for the observed damage to neurons and oligodendrocytes during multiple sclerosis (MS). Blocking adhesion molecules or preventing the effects of chemotactic mediators such as chemokines can be exploited to prevent immune cell recruitment to inflamed tissues. An anti-α4 integrin antibody (anti-VLA-4mAb/natalizumab (Tysabri®)) has been used as a treatment for MS and reduces leukocyte influx into the brain. In patients, anti-VLA-4 reduces relapses and disability progression. However, its mechanism of action in the brain is not completely understood. The anti-VLA-4mAb was demonstrated to mobilize hematopoietic progenitor cells. Interestingly, the chemokine SDF-1/CXCL12 and its receptor CXCR4 are also key factors regulating the migration of hematopoietic stem cells. Moreover, studies have revealed a crosstalk between SDF-1/CXCR4 and VLA-4 signaling in regulating cell migration. In this study, we address the effects of anti-VLA-4 on chemokine signaling in the brain during MS. We assessed the ability of anti-VLA-4 to regulate Experimental Autoimmune Encephalomyelitis (EAE) and chemokine/receptor signaling. Preclinical administration of anti-VLA-4 delayed clinical signs of EAE. We found that anti-VLA-4 treatment reduced chemokine expression. In order to further explore the interaction of anti-VLA-4 with chemokine/receptor signaling we used dual color transgenic mice. After EAE induction, the expression of both SDF-1/CXCL12 and CXCR4 receptor was upregulated, treatment with anti-VLA-4 inhibited this effect. The effects of anti-VLA-4 on chemokine signaling in the CNS may be of importance when considering its mechanism of action and understanding the pathogenesis of EAE. PMID: 24477403 [PubMed - as supplied by publisher]
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Related Articles Transplantation of Fas-deficient or wild-type neural stem/progenitor cells (NPCs) is equally efficient in treating experimental autoimmune encephalomyelitis (EAE). Am J Transl Res. 2014;6(2):119-28 Authors: Hackett C, Knight J, Mao-Draayer Y Abstract Studies have shown that neural stem/progenitor cell (NPC) transplantation is beneficial in experimental autoimmune encephalomyelitis (EAE), an established animal model of multiple sclerosis (MS). It is unclear whether NPCs have the ability to integrate into the host CNS to replace lost cells or if their main mechanism of action is via bystander immunomodulation. Understanding the mechanisms by which NPCs exert their beneficial effects as well as exploring methods to increase post-transplantation survival and differentiation is critical to advancing this treatment strategy. Using the EAE model and Fas-deficient (lpr) NPCs, we investigated the effects of altering the Fas system in NPC transplantation therapy. We show that transplantation of NPCs into EAE mice ameliorates clinical symptoms with greater efficacy than sham treatments regardless of cell type (wt or lpr). NPC transplantation via retro-orbital injections significantly decreased inflammatory infiltrates at the acute time point, with a similar trend at the chronic time point. Both wt and lpr NPCs injected into mice with EAE were able to home to sites of CNS inflammation in the periventricular brain and lumbar spinal cord. Both wt and lpr NPCs have the same capacity for inducing apoptosis of Th1 and Th17 cells, and minimal numbers of NPCs entered the CNS. These cells did not express terminal differentiation markers, suggesting that NPCs exert their effects mainly via bystander peripheral immunomodulation. PMID: 24489991 [PubMed]
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Related Articles The anti-VLA-4 antibody natalizumab induces erythroblastaemia in the majority of the treated patients with multiple sclerosis. Mult Scler. 2014 Feb 3; Authors: Robier C, Amouzadeh-Ghadikolai O, Bregant C, Diez J, Melinz K, Neubauer M, Quasthoff S Abstract The presence of erythroblasts in the peripheral blood is generally associated with severe underlying disorders. The anti-very late antigen-4 (anti-VLA-4) antibody natalizumab, which is approved for treatment of multiple sclerosis, mediates an increase in circulating haematopoietic stem cells and may also trigger erythroblastaemia. We investigated the prevalence of erythroblastaemia in sequential blood smears of 14 natalizumab-treated and 14 interferon-treated patients with multiple sclerosis. Erythroblastaemia was found in 13 natalizumab-treated subjects (93%), whereas all controls were negative (p<0.0001). Knowledge of this frequent side effect is crucial for the correct interpretation of blood smears in natalizumab-treated patients and to avoid unnecessary diagnostic procedures. PMID: 24493472 [PubMed - as supplied by publisher]
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Related Articles Feasibility of Cell Therapy in Multiple Sclerosis: A Systematic Review of 83 Studies. Int J Hematol Oncol Stem Cell Res. 2013;7(1):15-33 Authors: Ardeshiry Lajimi A, Hagh MF, Saki N, Mortaz E, Soleimani M, Rahim F Abstract Multiple Sclerosis is an inflammatory disease of the central nervous system in which T cells experience a second phase of activation, which ultimately leads to axonal demyelination and neurological disability. The recent advances in stem cell therapies may serve as potential treatments for neurological disorders. There are broad types of stem cells such as neural, embryonic, mesenchymal and hematopoietic stem cells with unprecedented hope in treating many debilitating diseases. In this paper we will review the substantial literature regarding experimental and clinical use of these stem cells and possible mechanisms in the treatment of MS. These results may pave the road for the utilization of stem cells for the treatment of MS. PMID: 24505515 [PubMed - as supplied by publisher]
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Related Articles Future treatment approaches to multiple sclerosis. Handb Clin Neurol. 2014;122:563-77 Authors: Derwenskus J, Lublin FD Abstract The modern treatment era for multiple sclerosis (MS) began in 1993 with the approval of the first disease-modifying agent. Since then the field has greatly expanded, with 10 therapies currently approved to treat MS. These treatments are effective to reduce relapses and changes on MRI, and slow disability. However, despite these medications some patients continue to have exacerbations, accumulate disability, and develop progressive disease due to partial effectiveness. New molecules with novel mechanisms of action and targets are being explored. Hopefully these agents will yield even greater efficacy without significant safety concerns. As more aggressive therapies are available to treat MS, the goals and expectations of treatment are also likely to change. Some of the emerging therapies, including alemtuzumab, daclizumab, rituximab, ocrelizumab, laquinimod, estriol, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), vitamin D, and stem cell transplantation, will be discussed in this chapter. In the future, therapies with different mechanisms may be combined, but this will need to be evaluated in clinical trials. Neuroprotection and repair definitely warrant further study. The future of MS treatment is very exciting, especially as our armamentarium expands. PMID: 24507535 [PubMed - in process]
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Related Articles T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014 Mar 3;124(3):1168-72 Authors: Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, de Paula Alves Sousa A, Griffith LM, Lim N, Nash RA, Turka LA Abstract Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCRβ chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. In CD4+ T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies. PMID: 24531550 [PubMed - in process]
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Related Articles Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014 Feb 19; Authors: Burman J, Iacobaeus E, Svenningsson A, Lycke J, Gunnarsson M, Nilsson P, Vrethem M, Fredrikson S, Martin C, Sandstedt A, Uggla B, Lenhoff S, Johansson JE, Isaksson C, Hägglund H, Carlson K, Fagius J Abstract BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. RESULTS: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres. PMID: 24554104 [PubMed - as supplied by publisher]
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Related Articles The Risk of Progressive Multifocal Leukoencephalopathy Under Biological Agents Used in the Treatment of Chronic Inflammatory Diseases. Inflamm Allergy Drug Targets. 2014 Feb 23; Authors: Toussirot E, Bereau M Abstract Biological agents such as monoclonal antibodies and soluble cytokine receptors have taken on an expanding role in the treatment of chronic immune mediated diseases. Progressive multifocal leukoencephalopathy (PML) is a rare central neurological disease caused by JC virus infection that has been described in the setting of conditions with severe impairment of immune surveillance, such as haematological malignancies, stem cell or solid organ transplantation and AIDS. This serious demyelinating disease has recently been described in patients receiving monoclonal antibodies for chronic inflammatory diseases such as multiple sclerosis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus or psoriasis. We review here the disease of PML, the different biological agents used in chronic inflammatory diseases that are associated with an increased risk of PML (natalizumab, rituximab, efalizumab and alemtuzumab), and the potential mechanisms that may explain the development of PML. Based on current knowledge of the biology of the JC virus and on the mechanisms of action of these biological agents, we discuss currently available tools that may be helpful in evaluating the risk of PML in this patient population. PMID: 24559124 [PubMed - as supplied by publisher]
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Related Articles Transplantation of human adipose-derived stem cells enhances remyelination in lysolecithin-induced focal demyelination of rat spinal cord. Mol Biotechnol. 2014 May;56(5):470-8 Authors: Ghasemi N, Razavi S, Mardani M, Esfandiari E, Salehi H, Zarkesh Esfahani SH Abstract Adipose-derived stem cells (ADSCs) are a desirable stem cell source in neurodegenerative diseases treatment due to their ability to differentiate into different cell lineages. In this study, we transplanted human ADSCs (hADSCs) into a lysophosphatidylcholine (lysolecithin) model of multiple sclerosis (MS) and determined the efficiency of these cells in remyelination process. Forty adult rats were randomly divided into control, lysolecithin, vehicle, and transplantation groups, and focal demyelination was induced by lysolecithin injection into spinal cord. To assess motor performance, all rats were examined weekly with a standard EAE scoring scale. Four weeks after cell transplantation, to assess the extent of demyelination and remyelination, Luxol Fast Blue staining was used. In addition, immunohistochemistry technique was used for assessment of the presence of oligodendrocyte phenotype cells in damaged spinal cord. Our results indicated that hADSCs had ability to differentiate into oligodendrocyte phenotype cells and improved remyelination process. Moreover, the evaluation of rat motor functions showed that animals which were treated with hADSC compared to other groups had significant improvement (P < 0.001). Our finding showed that hADSCs transplantation for cell-based therapies may play a proper cell source in the treatment of neurodegenerative diseases such as MS. PMID: 24570177 [PubMed - in process]
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Related Articles Serum-free spheroid suspension culture maintains mesenchymal stem cell proliferation and differentiation potential. Biotechnol Prog. 2014 Mar 10; Authors: Alimperti S, Lei P, Wen Y, Tian J, Campbell AM, Andreadis ST Abstract There have been many clinical trials recently using ex vivo-expanded human mesenchymal stem cells (MSCs) to treat several disease states such as graft-versus-host disease, acute myocardial infarction, Crohn's disease, and multiple sclerosis. The use of MSCs for therapy is expected to become more prevalent as clinical progress is demonstrated. However, the conventional 2-dimensional (2D) culture of MSCs is laborious and limited in scale potential. The large dosage requirement for many of the MSC-based indications further exacerbates this manufacturing challenge. In contrast, expanding MSCs as spheroids does not require a cell attachment surface and is amenable to large-scale suspension cell culture techniques, such as stirred-tank bioreactors. In the present study, we developed and optimized serum-free media for culturing MSC spheroids. We used Design of Experiment (DoE)-based strategies to systematically evaluate media mixtures and a panel of different components for effects on cell proliferation. The optimization yielded two prototype serum-free media that enabled MSCs to form aggregates and proliferate in both static and dynamic cultures. MSCs from spheroid cultures exhibited the expected immunophenotype (CD73, CD90, and CD105) and demonstrated similar or enhanced differentiation potential toward all three lineages (osteogenic, chondrogenic, adipogenic) as compared with serum-containing adherent MSC cultures. Our results suggest that serum-free media for MSC spheroids may pave the way for scale-up production of MSCs in clinically relevant manufacturing platforms such as stirred tank bioreactors. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 2014. PMID: 24616445 [PubMed - as supplied by publisher]
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Related Articles [Immunomodulatory properties of stem mesenchymal cells in autoimmune diseases.] Med Clin (Barc). 2014 Mar 14; Authors: Sánchez-Berná I, Santiago-Díaz C, Jiménez-Alonso J Abstract Autoimmune diseases are a cluster of disorders characterized by a failure of the immune tolerance and a hyperactivation of the immune system that leads to a chronic inflammation state and the damage of several organs. The medications currently used to treat these diseases usually consist of immunosuppressive drugs that have significant systemic toxic effects and are associated with an increased risk of opportunistic infections. Recently, several studies have demonstrated that mesenchymal stem cells have immunomodulatory properties, a feature that make them candidates to be used in the treatment of autoimmune diseases. In the present study, we reviewed the role of this therapy in the treatment of systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Crohn's disease and multiple sclerosis, as well as the potential risks associated with its use. PMID: 24636281 [PubMed - as supplied by publisher]
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Related Articles DMBA/TPA-Treatment is Necessary for BCC Formation from Patched Deficient Epidermal Cells in Ptch(flox/flox)CD4Cre(+/-) Mice. J Invest Dermatol. 2014 Mar 24; Authors: Uhmann A, Heß I, Frommhold A, König S, Zabel S, Nitzki F, Dittmann K, Lühder F, Christiansen H, Reifenberger J, Schulz-Schaeffer W, Hahn H Abstract The development of basal cell carcinoma (BCC), the most frequently diagnosed tumor among persons with European ancestry, is closely linked to mutations in the Hedgehog (Hh)-receptor and tumor suppressor Patched1 (Ptch). Using Ptch(flox/flox)CD4Cre(+/-) mice, in which Ptch was ablated in CD4Cre-expressing cells, we demonstrate that the targeted cells can give rise to BCC after treatment with 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA), but not after wounding of the skin. In addition, in this model BCC are not caused by malfunctioning of Ptch-deficient T cells since BCC did not develop when bone marrow (BM) of Ptch(flox/flox)CD4Cre(+/-) mice was transplanted into Ptch wildtype mice. Instead lineage tracing experiments and flowcytometric analyses suggest that the tumors are initiated from rare Ptch-deficient stem cell-like cells of the epidermis that express CD4. Since DMBA/TPA is a prerequisite for BCC development in this model, the initiated cells need a second stimulus for expansion and tumor formation. However, in contrast to papilloma this stimulus seems to be unrelated to alterations in the Ras-signaling cascade. Together these data suggest that biallelic loss of Ptch in CD4(+) cells does not suffice for BCC formation and that BCC formation requires a second so far unknown event, at least in the Ptch(flox/flox)CD4Cre(+/-) BCC mouse model.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.157. PMID: 24662765 [PubMed - as supplied by publisher]
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Related Articles The orally available, synthetic ether lipid edelfosine inhibits T cell proliferation and induces a type I interferon response. PLoS One. 2014;9(3):e91970 Authors: Abramowski P, Otto B, Martin R Abstract The drug edelfosine is a synthetic analog of 2-lysophosphatidylcholine. Edelfosine is incorporated by highly proliferating cells, e.g. activated immune cells. It acts on cellular membranes by selectively aggregating the cell death receptor Fas in membrane rafts and interference with phosphatidylcholine (PC) synthesis with subsequent induction of apoptosis. Edelfosine has been proposed for the treatment of autoimmune diseases like multiple sclerosis (MS). Earlier studies on the animal model of MS, experimental autoimmune encephalomyelitis (EAE), have generated first evidence for the efficacy of edelfosine treatment. However, it is unknown if the previously described mechanisms for edelfosine action, which are derived from in vitro studies, are solely responsible for the amelioration of EAE or if edelfosine may exert additional effects, which may be beneficial in the context of autoimmunity. Since it was the purpose of our studies to assess the potential usefulness of edelfosine for the treatment of MS, we examined its mechanism/s of action on immune functions in human T cells. Low doses of edelfosine led to a decrease in homeostatic proliferation, and further studies of the mechanism/s of action by genome-wide transcriptional profiling showed that edelfosine reduces the expression of MHC class II molecules, of molecules involved in MHC class II-associated processing and presentation, and finally upregulated a series of type I interferon-associated genes. The inhibition of homeostatic proliferation, as well as the effects on MHC class II expression and -presentation, and the induction of type I interferon-associated genes are novel and interesting in the context of developing edelfosine for clinical use in MS and possibly also other T cell-mediated autoimmune diseases. PMID: 24667731 [PubMed - in process]
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Related Articles Immunomodulatory effects of adipose-derived mesenchymal stem cells on the gene expression of major transcription factors in T cell subsets. Int Immunopharmacol. 2014 Apr 2; Authors: Mohammadzadeh A, Pourfathollah AA, Shahrokhi S, Hashemi SM, Moradi SL, Soleimani M Abstract It has been proposed that the immunomodulatory properties of mesenchymal stem cells (MSCs) play a crucial role in establishing and leading T lymphocytes, especially Th cell subsets, toward different functional subsets. To determine the effect of the immunomodulatory and regulatory functions of adipose-derived MSCs (AD-MSCs) on C57BL/6 spleen-isolated mononuclear cells (Spleen-MNCs), the gene expression of well-known effector and regulatory Th cell-related transcription factors, i.e., t-bet, GATA-3, Ror-γt and Foxp3, and their related cytokines, i.e., IFN-γ for Th1 cells, IL-4 for Th2 cells, IL-17 for Th17 cells and IL-10 and TGF-β for regulatory T cells, was studied using a co-culture condition system. The proliferation index of Spleen-MNCs was analyzed using a cell proliferation assay kit that utilized the CFSE staining method. Our findings indicate that AD-MSCs greatly impact the up-regulation of immunomodulatory cytokines, such as TGF-β (p<0.001), and the down-regulation of inflammatory cytokines, such as IFN-γ (p<0.005), and transcription factors, such as t-bet (p<0.001). Considering the immunomodulatory effects of MSCs in the differentiation of Th cell subsets, understanding and harnessing this property of MSCs could be a powerful strategy in the treatment of inflammatory autoimmune diseases such as multiple sclerosis. PMID: 24704622 [PubMed - as supplied by publisher]
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