RETRACTED: Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation (Retracted article. See vol. 13, 2022)

Background: esenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional beta-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. Methods: Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on beta-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. Results: Our results showed that bmMDEs reversed diabetic beta-cell dedifferentiation and improved beta-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved beta-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of beta-catenin signaling in beta-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve beta-cell function. Conclusions: These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic beta-cell dysfunction by acting on the NUMB/beta-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM.