MiR-375 Promotes Redifferentiation of Adult Human β Cells Expanded In Vitro

In-vitro expansion of beta cells from adult human pancreatic islets could provide abundant cells for cell replacement therapy of diabetes. However, proliferation of beta-cell-derived (BCD) cells is associated with dedifferentiation. Here we analyzed changes inmicroRNAs (miRNAs) during BCD cell dedifferentiation and identified miR-375 as one of the miRNAs greatly downregulated. We hypothesized that restoration of miR-375 expression in expanded BCD cells may contribute to their redifferentiation. Our findings demonstrate that overexpression of miR-375 alone leads to activation of beta-cell gene expression, reduced cell proliferation, and a switch from N-cadherin to E-cadherin expression, which characterizes mesenchymal-epithelial transition. These effects, which are reproducible in cells derived from multiple human donors, are likely mediated by repression of PDPK1 transcripts and indirect downregulation of GSK3 activity. These findings support an important role of miR-375 in regulation of human beta-cell phenotype, and suggest that miR-375 upregulation may facilitate the generation of functional insulin-producing cells following ex-vivo expansion of human islet cells.