期刊
STEM CELL RESEARCH & THERAPY
卷 12, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13287-021-02371-0
关键词
Exosome; Mesenchymal stem cell; Type 2 diabetes mellitus; beta-cell dedifferentiation; miR-146a
资金
- National Natural Science Foundation of China [82070800, 81670706, 81873632, 81770818, 81800736, 81800727, 81900756]
- National Key R&D Program of China [2016YFC0901204, 2018YFC1311801]
- Taishan Scholars Foundation of Shandong Province [ts201712089]
- Natural Science Foundation of Shandong Province [ZR2019BH018, ZR2019PH078]
Exosomes derived from bone marrow mesenchymal stem cells (bmMSCs) contain miR-146a which acts on the NUMB/beta-catenin signaling pathway to protect against diabetic beta-cell dysfunction, potentially representing a novel therapeutic strategy for type 2 diabetes mellitus.
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.
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