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Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation. | LitMetric

Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation.

Stem Cell Res Ther

Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China.

Published: August 2021

AI Article Synopsis

  • Mesenchymal stem cells (MSCs) may help treat type 2 diabetes not by becoming β-cells, but through their exosomes, which have paracrine functions that can influence other cells.
  • In experiments with T2DM rats and glucose-treated islets, exosomes from bone marrow MSCs (bmMDEs) reversed β-cell dedifferentiation and improved insulin secretion, with a specific focus on the miRNA miR-146a.
  • The study identified that miR-146a protects β-cells by targeting the protein Numb, activating the β-catenin signaling pathway, suggesting this mechanism could be a new therapeutic approach for managing T2DM.

Article Abstract

Background: Mesenchymal 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 β-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 β-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 β-cell dedifferentiation and improved β-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 β-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of β-catenin signaling in β-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve β-cell function.

Conclusions: These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic β-cell dysfunction by acting on the NUMB/β-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356465PMC
http://dx.doi.org/10.1186/s13287-021-02371-0DOI Listing

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