We show that extracellular vesicles (EVs) released by mesenchymal cells (i.e., fibro–adipogenic progenitors—FAPs) mediate microRNA (miR) transfer to muscle stem cells (MuSCs) and that exposure of dystrophic FAPs to HDAC inhibitors (HDACis) increases the intra‐EV levels of a subset of miRs, which cooperatively target biological processes of therapeutic interest, including regeneration, fibrosis, and inflammation. Increased levels of miR‐206 in EVs released by FAPs of muscles from Duchenne muscular dystrophy (DMD) patients or mdx mice exposed to HDACi are associated with enhanced regeneration and decreased fibrosis. Consistently, EVs from HDACi‐treated dystrophic FAPs can stimulate MuSC activation and expansion ex vivo, and promote regeneration, while inhibiting fibrosis and inflammation of dystrophic muscles, upon intramuscular transplantation in mdx mice, in vivo. AntagomiR‐mediated blockade of individual miRs reveals a specific requirement of miR‐206 for EV‐induced expansion of MuSCs and regeneration of dystrophic muscles, and indicates that cooperative activity of HDACi‐induced miRs accounts for the net biological effect of these EVs. These data point to pharmacological modulation of EV content as novel strategy for therapeutic interventions in muscular dystrophies.

中文翻译：

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HDAC 抑制剂在营养不良的肌肉驻留间充质细胞的细胞外囊泡中调节 miRNA。

我们表明间充质细胞（即纤维脂肪生成祖细胞 FAPs）释放的细胞外囊泡（EVs）介导 microRNA（miR）转移到肌肉干细胞（MuSCs），并且营养不良的 FAPs 暴露于 HDAC 抑制剂（HDACis）会增加内‐miRs 子集的 EV 水平，它们协同靶向具有治疗意义的生物过程，包括再生、纤维化和炎症。Duchenne 型肌营养不良症 (DMD) 患者或暴露于 HDACi 的 mdx 小鼠肌肉的 FAP 释放的 EV 中 miR-206 水平升高与增强再生和减少纤维化有关。一致地，来自 HDACi 治疗的营养不良 FAP 的 EV 可以刺激 MuSC 激活和体外扩增在 mdx 小鼠体内进行肌肉移植后，促进再生，同时抑制营养不良肌肉的纤维化和炎症。个体miR的RNA拮抗剂介导的封锁揭示的miR-206的MuSCs的EV-诱导扩张和营养不良的肌肉再生的具体要求小号，并表明的HDACi诱导miR的合作活动占这些电动汽车的净生物学效应。这些数据表明，EV 含量的药理学调节是肌营养不良症治疗干预的新策略。