Extracellular vesicles derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells alleviate immune thrombocytopenia by inhibiting T helper 17 differentiation
Extracellular vesicles derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells alleviate immune thrombocytopenia by inhibiting T helper 17 differentiation
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源自 miR-199a-5p 修饰的脂肪间充质干细胞的细胞外囊泡通过抑制 T 辅助细胞 17 分化缓解免疫性血小板减少症
DOI：
10.1038/s41374-020-00515-z
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发表时间：
2021-01-05
影响因子：
5
通讯作者：
Wang, Zhaoyue
中科院分区：
文献类型：
--
作者：
Li, Jianqin;Xia, Yanlin;Wang, Zhaoyue
Th 17细胞的异常分化是免疫性血小板减少症（ITP）进展的重要促进剂。在这项研究中，作者发现miR-199 a-5 p在ITP期间下调。补充miR-199 a-5 p修饰的ADSC来源的细胞外囊泡（EVs）可通过将miR-199 a-5 p转移至CD 4（+）T细胞而显著抑制Th 17分化，从而改善实验性ITP。因此，本研究探讨了miR-199 a-5 p在Th 17分化中的作用，并确定了来自miR-199 a-5 p修饰的脂肪间充质干细胞（ADSC）的细胞外囊泡（EV）是否可以通过抑制Th 17分化来缓解ITP。ITP小鼠脾组织中miR-199 a-5 p水平降低，而CD 4（+）T细胞中信号转导和转录激活因子3（STAT 3）表达和Th 17群体增加。在功能上，miR-199 a-5 p过表达降低了IL-17分泌和Th 17/CD 4（+）T细胞的比例。进一步的研究表明miR-199 a-5 p直接靶向STAT 3 mRNA，并负调控其表达。发现STAT 3过表达促进Th 17分化，其随后被miR-199 a-5 p过表达消除。从miR-199 a-5 p修饰的ADSC中分离的EV（miR-199 a-5 p-EVs）高表达miR-199 a-5 p，并且在体外可以抑制向Th 17表型极化的CD 4（+）T细胞。施用miR-199 a-5 p-EV可升高ITP小鼠的血小板计数并降低Th 17/CD 4（+）T细胞的比例。总之，来自miR-199 a-5 p修饰的ADSC的EV通过将miR-199 a-5 p转移到CD 4（+）T细胞而生动地抑制了Th 17分化，从而改善了实验性ITP。
The abnormal differentiation of Th17 cells is a vital promoter of immune thrombocytopenia (ITP) progression. In this study, the authors found that miR-199a-5p is downregulated during ITP. Supplementation of extracellular vesicles (EVs) derived from miR-199a-5p-modified ADSCs markedly repress Th17 differentiation by transferring miR-199a-5p to CD4(+)T cells, thus ameliorating experimental ITP.The abnormal differentiation of T helper 17 (Th17) cells is considered a vital promoter of immune thrombocytopenia (ITP) progression. Therefore, this study investigated the role of miR-199a-5p in Th17 differentiation and determined whether extracellular vesicles (EVs) derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells (ADSCs) could relieve ITP by inhibiting Th17 differentiation. The miR-199a-5p level was lessened in the spleen tissues of mice with ITP, while the signal transducer and activator of transcription 3 (STAT3) expression and the population of Th17 in CD4(+)T cells were boosted. Functionally, miR-199a-5p overexpression lowered IL-17 secretion and the proportion of Th17/CD4(+)T cells. Further investigation showed that miR-199a-5p directly targeted STAT3 mRNA, and negatively modulated its expression. STAT3 overexpression was found to facilitate Th17 differentiation, which was subsequently abolished by miR-199a-5p overexpression. EVs isolated from miR-199a-5p-modified ADSCs (miR-199a-5p-EVs) highly expressed miR-199a-5p and could restrain CD4(+)T cells polarized toward a Th17 phenotype in vitro. Administering of miR-199a-5p-EVs elevated platelet counts and decreased the proportion of Th17/CD4(+)T cells in mice with ITP. Taken together, EVs derived from miR-199a-5p-modified ADSCs vividly repressed Th17 differentiation by transferring miR-199a-5p to CD4(+)T cells, thus ameliorating experimental ITP.