Allogeneic islet transplantation is an option to treat diabetes however there are obstacles that are limiting its clinical use. We have examined whether mesenchymal stem cells (MSC) improve islet graft survival and whether such therapy allows for better graft acceptance with reduced requirement for immunosuppression. In vitro-expanded syngeneic bone marrow-derived MSC were co-transplanted with islets into omental pouch in a rat model of streptozotocin-induced diabetes. Marginal mass syngeneic islet transplantation into the omentum with MSC promoted sustained normoglycemia. Interestingly, allogeneic islets +MSC, but not islets alone, with short-term use of immunosuppression enhanced long-term islet graft survival, insulin expression in the grafts and induced normal serum insulin levels and normoglycemia. T cells from recipients transplanted with allogeneic islets +MSC produced low levels of IFN-gamma and TNF-alpha upon ex-vivo activation, and this transplantation protocol promoted the generation of IL-10-secreting CD4(+) T cells. These data encourage further preclinical and eventually, clinical MSC-based islet transplantation to improve the outcome of allogeneic islet transplantation in the treatment of diabetes.
"In turn, MSCs are able to affect pancreatic islets' behavior, but through some different mechanisms. The MSC coating improves the health condition of pancreatic islets, probably by preserving membrane integrity  and by releasing trophic factors –, while indirect co-cultures are able to increase islets' survival, but not insulin release. These results are basically different from those obtained by Jung et al.  who observed increased islet survival only in direct co-cultures with MSCs. "
[Show abstract][Hide abstract] ABSTRACT: The clinical usability of pancreatic islet transplantation for the treatment of type I diabetes, despite some encouraging results, is currently hampered by the short lifespan of the transplanted tissue. In vivo studies have demonstrated that co-transplantation of Mesenchymal Stem Cells (MSCs) with transplanted pancreatic islets is more effective with respect to pancreatic islets alone in ensuring glycemia control in diabetic rats, but the molecular mechanisms of this action are still unclear.
The aim of this study was to elucidate the molecular mechanisms of the positive effect of MSCs on pancreatic islet functionality by setting up direct, indirect and mixed co-cultures.
MSCs were both able to prolong the survival of pancreatic islets, and to directly differentiate into an “insulin-releasing” phenotype. Two distinct mechanisms mediated these effects: i) the survival increase was observed in pancreatic islets indirectly co-cultured with MSCs, probably mediated by the trophic factors released by MSCs; ii) MSCs in direct contact with pancreatic islets started to express Pdx1, a pivotal gene of insulin production, and then differentiated into insulin releasing cells. These results demonstrate that MSCs may be useful for potentiating pancreatic islets' functionality and feasibility.
PLoS ONE 01/2014; 9(1):e84309. DOI:10.1371/journal.pone.0084309 · 3.23 Impact Factor
"Co-infusion of MSCs with donor bone marrow has been shown to enhance mixed chimerism, reverse GVHD, and improve vascularized skin grafts in rats (Aksu et al., 2008). In a rat islet transplantation model, Solari et al. (2009) demonstrated long-term islet allograft survival, normal serum insulin levels, and normoglycemia when autologous MSCs were co-transplanted with marginal islet masses. Promising results from a phase II clinical trial showed that 39 of 55 patients with steroid-resistant, severe acute GVHD responded to MSC therapy and experienced a significant survival benefit (Le Blanc et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Since the concept of immunologic tolerance was discovered in the 1940s, the pursuit of tolerance induction in human transplantation has led to a rapid development of pharmacologic and biologic agents. Short-term graft survival remains an all-time high, but successful withdrawal of immunosuppression to achieve operational tolerance rarely occurs outside of liver transplantation. Collaborative efforts through the NIH sponsored Immune Tolerance Network and the European Commission sponsored Reprogramming the Immune System for Establishment of Tolerance consortia have afforded researchers opportunity to evaluate the safety and efficacy of tolerogenic strategies, investigate mechanisms of tolerance, and identify molecular and genetic markers that distinguish the tolerance phenotype. In this article, we review traditional and novel approaches to inducing tolerance for organ transplantation, with an emphasis on their translation into clinical trials.
Frontiers in Immunology 07/2012; 3:198. DOI:10.3389/fimmu.2012.00198
"During solid organ transplantation, to prevent transplant rejection, the individual has to be under a life-long non-specific immunosuppressive therapy that may tend to lots of complications. It has been shown in variety of animal models, that using MSC could prevent rejection and induce prolong graft acceptance or at least minimize dependency on long-term use of immunosuppressive drugs following the transplantation; consequently, prevent the significant side effects of immunosuppressive drugs’ administration such as drug toxicity, opportunistic infections and malignancies.1011 The most promising results of clinical application of MSC have been observed in bone marrow (BM) transplantation; here they not only prevent and ameliorate graft-versus-host disease (GVHD), but also increase BM engraftment and improve its function.23 "
[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cells or "multipotent stromal cells" are heterogeneous cell population with self-renewal and multilinage differentiation. The aim of this study was to examine and compare the expression of important stem cell surface markers on two populations of mesenchymal stem cells, one derived from human exfoliated deciduous teeth and the other derived from human adipose tissue. These new stem cells will offer a promising avenue for prevention and reversal of many human diseases such as type 1 diabetes and prevention of liver fibrotic process.
Mesenchymal stem cells were isolated and cultured from human adipose tissue and dental pulp of human exfoliated deciduous teeth. The cultured cells then were harvested and stained by different fluorescent labeled monoclonal antibodies against surface markers and were analyzed using flow cytometry.
Both different cell populations expressed CD44, CD90 and CD13 (stem cell markers) with similar intensity. They did not express hematopoietic markers (CD11b, CD19 and CD34), and lymphocyte or leukocyte antigens CD3, CD7, CD20, CD14, CD45, CCR5 (CD195), CD11b and CD10 on their surfaces. Two different cell types demonstrated different levels of expression in CD56 and CD146. Mesenchymal stem cells from human exfoliated deciduous teeth were positive for CD105 and were negative for CCR3 and CCR4 expression.
Both cell populations derived from adipose tissue and dental pulp showed common phenotypic markers of mesenchymal stem cells. In conclusion, mesenchymal stem cells could be isolated and cultured successfully from dental pulp of human exfoliated deciduous teeth, they are very good candidates for treatment and prevention of human diseases.
International journal of preventive medicine 03/2010; 1(3):164-71.
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