Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro.
ABSTRACT It was recently reported that pluripotent mesenchymal stem cells (MSCs) in rodent bone marrow (BM) have the capacity to generate insulin-producing cells (IPCs) in vitro. However, little is known about this capacity in human BM-MSCs. We developed a nongenetic method to induce human BM-MSCs to transdifferentiate into IPCs both phenotypically and functionally. BM-MSCs from 12 human donors were sequentially cultured in specially defined conditions. Their differentiation extent toward beta-cell phenotype was evaluated systemically. Specifically, after induction human BM-MSCs formed spheroid islet-like clusters containing IPCs, which was further confirmed by dithizone (DTZ) staining and electron microscopy. These IPCs expressed multiple genes related to the development or function of pancreatic beta cells (including NKX6.1, ISL-1, Beta2/Neurod, Glut2, Pax6, nestin, PDX-1, ngn3, insulin and glucagon). The coexpression of insulin and c-peptide was observed in IPCs by immunofluorescence. Moreover, they were able to release insulin in a glucose-dependent manner and ameliorate the diabetic conditions of streptozotocin (STZ)-treated nude mice. These results indicate that human BM-MSCs might be an available candidate to overcome limitations of islet transplantation.
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ABSTRACT: The worldwide increase in the prevalence of Diabetes mellitus (DM) has highlighted the need for increased research efforts into treatment options for both the disease itself and its associated complications. In recent years, mesenchymal stromal cells (MSCs) have been highlighted as a new emerging regenerative therapy due to their multipotency but also due to their paracrine secretion of angiogenic factors, cytokines, and immunomodulatory substances. This review focuses on the potential use of MSCs as a regenerative medicine in microvascular and secondary complications of DM and will discuss the challenges and future prospects of MSCs as a regenerative therapy in this field. MSCs are believed to have an important role in tissue repair. Evidence in recent years has demonstrated that MSCs have potent immunomodulatory functions resulting in active suppression of various components of the host immune response. MSCs may also have glucose lowering properties providing another attractive and unique feature of this therapeutic approach. Through a combination of the above characteristics, MSCs have been shown to exert beneficial effects in pre-clinical models of diabetic complications prompting initial clinical studies in diabetic wound healing and nephropathy. Challenges that remain in the clinical translation of MSC therapy include issues of MSC heterogeneity, optimal mode of cell delivery, homing of these cells to tissues of interest with high efficiency, clinically meaningful engraftment, and challenges with cell manufacture. An issue of added importance is whether an autologous or allogeneic approach will be used. In summary, MSC administration has significant potential in the treatment of diabetic microvascular and secondary complications but challenges remain in terms of engraftment, persistence, tissue targeting, and cell manufacture.Frontiers in Endocrinology 01/2014; 5:86.
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ABSTRACT: Human mesenchymal stromal cells (MSCs) are being used in clinical trials, but the best protocol to prepare the cells for administration to patients remains unclear. We previously demonstrated that MSCs could be pre-activated to express therapeutic factors by culturing the cells in 3 dimensions (3D). We compared the activation of MSCs in 3D in fetal bovine serum containing medium and in multiple xeno-free media formulations.Cytotherapy 09/2014; · 3.06 Impact Factor
Article: Cell Therapy in Type 1 Diabetes[Show abstract] [Hide abstract]
ABSTRACT: The incidence of diabetes mellitus has grown exponentially in the last few years. Etiopathogenesis of diabetes implies a β-cells damage in the islet of Langerhans, either through an autoimmune reaction present in type 1 diabetic patients or through altered function within these cells that affect their ability to secrete a properly functioning insulin hormone, in patients suffering from type 2 diabetes. Exogenous insulin supply is, at the moment, the therapy of choice of the disease but it does not allow tight control of glucose regulation, leading to long-term complications. Over the past few decades, pancreas or pancreas-kidney organ transplantation has been the most effective treatment for severe diabetic patients. Recently, an alternative promising therapeutic approach, consisting of successful pancreatic islet transplantation to reconstitute the insulin producing β cells, has also emerged. Unfortunately the number of donor islets is too low compared to high number of patients needing a transplant, so the search for new renewable sources of high-quality β-cells becomes highly topical. In this review, starting from the description of state of art of islet transplantation, we summarize the more recent promising approaches to the generation of new β-cells giving a big enfacy to adult stem/progenitor cells. Abbreviations: ADSCs (adipose derived stem cells): BM (bone marrow): EPCs (endothelial progenitor cells): ESRD (end stage renal disease): ESCs (embryonic stem cells): IAK (islet transplantation after kidney grafting): HGF (hepatocyte growth factor): hPDMSCs (human placenta derived mesenchymal stem cells): HSCs (hematopoietic stem cells): IPCCs (insulin producing cell clusters): IPSs (induced pluripotent stem cells): MSCs (mesenchymal stem cells): STZ (streptozotocin).Journal of Stem Cell Research & Therapy. 01/2011; 01(S2).