Mesenchymal Stem Cells Cooperate with Bone Marrow Cells in Therapy of Diabetes

Abstract

Several recent studies have suggested that the adult bone marrow harbors cells that can influence ␤-cell regeneration in diabetic animals. Other reports, however, have contradicted these findings. To address this issue, we used an animal model of type 1 diabetes in which the disease was induced with streptozotocin in mice. Freshly prepared sexmismatched bone marrow cells (BMCs) and syngeneic or allogeneic mesenchymal stem cells (MSCs) were concomitantly administrated into sublethally irradiated diabetic mice. Blood glucose and serum insulin concentrations rapidly returned to normal levels, accompanied by efficient tissue regeneration after a single injection of a mixture of 10 6 BMCs per 10 5 MSCs. Neither BMC nor MSC transplantation was effective alone. Successful treatment of diabetic animals was not due to the reconstitution of the damaged islet cells from the transplant, since no donor-derived ␤-cells were found in the recovered animals, indicating a graftinitiated endogenous repair process. Moreover, MSC injection caused the disappearance of ␤-cell-specific T lymphocytes from diabetic pancreas. Therefore, we suggest that two aspects of this successful treatment regimen operate in parallel and synergistically in our model. First, BMCs and MSCs induce the regeneration of recipient-derived pancreatic insulin-secreting cells. Second, MSCs inhibit T-cell-mediated immune responses against newly formed ␤-cells, which, in turn, are able to survive in this altered immunological milieu. Thus, the application of this therapy in human patients suffering from diabetes and/or other tissue destructive autoimmune diseases may be feasible. STEM CELLS 2008;26:244 -253 Disclosure of potential conflicts of interest is found at the end of this article.

The Effect of In Vivo Mobilization of Bone Marrow Stem Cells on the Pancreas of Diabetic Albino Rats (A Histological & Immunohistochemical Study)

“…This may be due to attraction of stem cells by the diabetic pancreas. This finding was explained by Körbling et al (27) (34) reported that administration of BMCs with MSCs normalized the blood glucose level and serum insulin levels in STZ-induced diabetic mice. This allowed regeneration of recipient-derived pancreatic insulin-secreting cells.…”

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells

“…One possible explanation for this efficacy could be related to the regeneration of pancreatic islets by MSCs; however, we considered this hypothesis unlikely since protection was obtained during the early inflammatory phase of the disease. Moreover, Urban et al [31] have recently reported in a streptozotocin-induced mouse model of diabetes that MSCs cannot induce pancreas regeneration by themselves, as they require co-injection of bone marrow stem cells. In addition, clinical efficacy in our model was correlated with greatly decreased insulitis scores, further suggesting immune-mediated, rather than regenerative, mechanisms.…”

Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks

“…75 Similarly, co-infusion of MSCs and BM cells, following sublethal irradiation, inhibited the proliferation of b-cell-specific T cells isolated from the pancreas of diabetic mice and restored insulin and glucose levels through the induction of regenerated recipient-derived pancreatic b-cells in the absence of transdifferentiation. 76 The immunosuppressive effect of MSCs on T cells was also exploited in a multi-organ autoimmunity mouse model in which MSCs homed in the mesenteric lymph nodes, significantly improving autoimmune enteropathy. 77 These results confirm the therapeutic plasticity of MSCs owing to their capacity of modulating systemic autoimmunity and protecting target tissues.…”