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

• Published in: Stem cell research & therapy 2021-08, Vol.12 (1), p.1-449
• Main Authors: He, Qin, Song, Jia, Chen, Cui, Wang, Jinbang, Hu, Huiqing, Guo, Xinghong, Yang, Mengmeng, Wang, Lingshu, Yan, Fei, Liang, Kai, Liu, Zhaojian, Liu, Fuqiang, Sun, Zheng, Dong, Ming, Hou, Xinguo, Chen, Li
• Format: Article
• Language: English
• Subjects: Apoptosis; Beta cells; Bone marrow; Cell differentiation; Cell fate; Diabetes; Diabetes mellitus (non-insulin dependent); Exosome; Exosomes; Experiments; Extracellular vesicles; Fasting; Glucose; Insulin; Insulin resistance; Insulin secretion; Membrane proteins; Mesenchymal stem cell; Mesenchymal stem cells; MicroRNAs; miR-146a; miRNA; Paracrine signalling; Reporter gene; Secretion; Signal transduction; Stem cell transplantation; Stem cells; Type 2 diabetes mellitus; Veins & arteries; β-Catenin; β-cell dedifferentiation
• ISSN: 1757-6512
• DOI: 10.1186/s13287-021-02371-0

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.