由 miR-199a-5p 修饰的脂肪间充质干细胞来源的细胞外囊泡通过抑制辅助性 T 细胞 17 分化缓解免疫性血小板减少症。
Extracellular vesicles derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells alleviate immune thrombocytopenia by inhibiting T helper 17 differentiation.
机构信息
Hematology Department, The Children's Hospital of Soochow University, Suzhou, 215000, China.
The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, 215000, China.
出版信息
Lab Invest. 2021 Mar;101(3):318-327. doi: 10.1038/s41374-020-00515-z. Epub 2021 Jan 5.
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 CD4T cells were boosted. Functionally, miR-199a-5p overexpression lowered IL-17 secretion and the proportion of Th17/CD4T 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 CD4T cells polarized toward a Th17 phenotype in vitro. Administering of miR-199a-5p-EVs elevated platelet counts and decreased the proportion of Th17/CD4T 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 CD4T cells, thus ameliorating experimental ITP.
辅助性 T 细胞 17（Th17）细胞的异常分化被认为是免疫性血小板减少症（ITP）进展的重要促进因素。因此，本研究探讨了 miR-199a-5p 在 Th17 分化中的作用，并确定源自 miR-199a-5p 修饰的脂肪间充质干细胞（ADSCs）的细胞外囊泡（EVs）是否可以通过抑制 Th17 分化来缓解 ITP。ITP 小鼠的脾脏组织中 miR-199a-5p 水平降低，而信号转导和转录激活因子 3（STAT3）表达和 CD4T 细胞中的 Th17 细胞群增加。功能上，miR-199a-5p 过表达降低了 IL-17 的分泌和 Th17/CD4T 细胞的比例。进一步研究表明，miR-199a-5p 可直接靶向 STAT3 mRNA，并负调控其表达。发现 STAT3 过表达可促进 Th17 分化，而 miR-199a-5p 过表达可使其失活。从 miR-199a-5p 修饰的 ADSCs 中分离出的 EV（miR-199a-5p-EVs）高度表达 miR-199a-5p，可在体外抑制 CD4T 细胞向 Th17 表型极化。在 ITP 小鼠中给予 miR-199a-5p-EVs 可提高血小板计数并降低 Th17/CD4T 细胞的比例。综上所述，源自 miR-199a-5p 修饰的 ADSCs 的 EV 通过将 miR-199a-5p 转移至 CD4T 细胞来显著抑制 Th17 分化，从而改善实验性 ITP。
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