Abstract
Autoimmune destruction of pancreatic beta cells causes absolute insulin deficiency and results in type 1 diabetes mellitus (T1DM). The substitution of healthy pancreatic beta cells for damaged cells would be the ideal treatment for T1DM; thus, the generation of pancreatic beta cells from adult stem cells represents an attractive avenue for research. In this study, a cocktail of factors was used to induce the differentiation of pancreatic beta cells from mesenchymal stem cells (MSCs). The differentiation program was divided into five stages, and the roles of the cocktail factors used during each stage were systematically elucidated. Activin A was found to phosphorylate Smad2 and Smad3 in stage III, thereby activating the TGF-β/Smad pathway. Meanwhile, the endocrine-specific transcription factor, Ngn3, and the pancreas-specific miRNAs, miR-375 and miR-26a, were dramatically elevated in stage III. We next demonstrated that Smad4, an important transcription factor in the TGF-β/Smad pathway, could bind to the promoter sequences of target genes and enhance their transcription to initiate the differentiation of beta cells. Use of SB-431542, an inhibitor of the TGF-β/Smad pathway, demonstrated in vivo and in vitro that this pathway plays a critical role in the production of pancreatic beta cells and in modulating insulin secretion. Thus, the TGF-β/Smad pathway is involved in the production of beta cells from adult stem cells by enhancing the transcription of Ngn3, miR-375, and miR-26a. These findings further underline the significant promise of cell transplant therapies for type 1 diabetes mellitus.
Highlights
Pancreatic beta cells regulate blood glucose homeostasis through their production of insulin
Combining our data with those from previous reports, we found that the pancreatic miRNAs, miR-26a and miR-375, play an important role in the formation of beta cells and in their secretion of insulin (Bai et al, 2017a,b), and that the TGF-β/Smad pathway plays an important role in regulating the transcription of these pancreatic miRNAs
Based on flow cytometry (FCM), the mice umbilical cord mesenchymal stem cells (MSCs) were positive for specific markers of MSCs including CD44, CD90, and CD105 (Figure 1A) but negative for specific
Summary
Pancreatic beta cells regulate blood glucose homeostasis through their production of insulin. Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of pancreatic beta cells. The replacement of these beta cells with healthy cells would be the ideal therapy for T1DM; the production of pancreatic beta cells from adult stem cells or embryonic stem cells offers a promising avenue for research. TGF-β/Smad Pathway in Beta Cell Differentiation tissue is readily obtained from discarded term placentae without any risk to the donors. Umbilical cord MSCs are typical adult MSCs but with the added advantages of being easy to culture in vitro and of simpler ethical access compared with other stem cells. Umbilical cord MSCs are a promising candidate for cell therapy
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