Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factors.

Abstract

BackgroundSTAT3 has been demonstrated to play a role in maintaining cellular identities in the pancreas, whereas an activating STAT3 mutation has been linked to impaired β-cell function.MethodsThe role of STAT3 in β-cell neogenesis, induced by the exogenous expression of Pdx1, Neurog3, and Mafa, was analyzed in vitro and in vivo.FindingsThe expression of phosphorylated STAT3 (pSTAT3) was induced in both Pdx1-expressing and Mafa-expressing cells, but most of the induced β cells were negative for pSTAT3. The suppression of STAT3 signaling, together with exogenously expressed Pdx1, Neurog3, and Mafa, significantly increased the number of reprogrammed β cells in vitro and in vivo, enhanced the formation of islet-like clusters in mice, and ameliorated hyperglycemia in diabetic mice.InterpretationThese findings suggest that STAT3 inhibition promotes cellular reprogramming into β-like cells, orchestrated by defined transcription factors, which may lead to the establishment of cell therapies for curing diabetes.FundJSPS, MEXT, Takeda Science Foundation, Suzuken Memorial Foundation, Astellas Foundation for Research on Metabolic Disorders, Novo Nordisk, Eli Lilly, MSD, Life Scan, Novartis, and Takeda.