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

Stem Cell Research & Therapy

Zhaojian Liu¹  Chen Cui²  Jia Song²  Fei Yan²  Mengmeng Yang²  Huiqing Hu²  Xinghong Guo²  Fuqiang Liu²  Zheng Sun²  Kai Liang²  Qin He²  Lingshu Wang²  Jinbang Wang²  Xinguo Hou³  Ming Dong³  Li Chen⁴ 

[1] Department of Cell Biology, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China;Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, 250012, Jinan, Shandong, China;Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, 250012, Jinan, Shandong, China;Institute of Endocrine and Metabolic Diseases of Shandong University, 250012, Jinan, China;Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, 250012, Jinan, China;Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, 250012, Jinan, Shandong, China;Institute of Endocrine and Metabolic Diseases of Shandong University, 250012, Jinan, China;Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, 250012, Jinan, China;Jinan Clinical Research Center for Endocrine and Metabolic Diseases, 250012, Jinan, China;

关键词: Exosome;    Mesenchymal stem cell;    Type 2 diabetes mellitus;    β-cell dedifferentiation;    miR-146a;   

DOI  :  10.1186/s13287-021-02371-0

来源: Springer

【 摘 要 】

BackgroundMesenchymal 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.MethodsBone 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.ResultsOur 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.ConclusionsThese 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.

【 授权许可】

CC BY