Allogenic BM-MSC Infusion Ignites α To β Conversion In STZ-induced Diabetic Rat：a New Paradigm To Change Diabetes

Deficiency of β-cell mass and failure of islet function are major characteristics in bothtype1and type2diabetes. Therefore, endogenous β-cell mass restoration and isletfunction reconstruction hold great promise for diabetic therapy. Numerous studies haveshowed that infusion of bone marrow-derived mesenchymal stem cells (BM-MSCs) canefficiently ameliorate hyperglycemia in diabetic models and restore the β-cell mass;however, the bona fide origin of the de novo generated β-cell and the mechanism involvedare largely unknown. We hypothesized that the augmentation of β-cell mass induced byMSC infusion may, at least in part, emanate from duplication of pre-existing β-cells ortrans-differentiation of non-β-cells within the pancreas by possibly the secretory effects ofMSCs. In this study, the diabetic animal model was induced by single high dose of STZ(65mg/kg, i.p.) injection, and the BM-MSCs which were extracted from the allogeneic ratswere cultured in vitro to third-passage, then the MSCs or supernatant of MSCs weretransfused into diabetic rat intravenously respectively. The infusion of BM-MSCs duringearly phase but not late phase resulted in a significant endogenous β-cell regeneration andislet architecture restoration, leading to a gradual and sustained amelioration of elevatedblood glucose. Direct conversion from cell to β-cell accounted for the neogenic β-cells,and considerable number of intermediate cells co-expressing and β-cell specific markers(glucagon/insulin, glucagon/PDX-1, and MafB/insulin double positive cells) witnessed thisextraordinary cell type transition. In addition, transfusion of MSCs’supernatant promotedappearance of such intermediate cells as well, yet hardly induced β-cell regeneration andlowered blood glucose in diabetic rats. Our data first reported that directtransdifferentiation from-cell into-cell as the major, if not only, mechanism for β-cellregeneration induced by MSC infusion during early phase through its secretory effect.Successful identification of-cell as the cellular origin of newborn β-cells after MSCinfusion would reinforce the basis of MSC-based diabetic treatment, and the intriguingconversion from to β-cell could doubtlessly provide a revolutionary paradigm to curing diabetes.