期刊
EMBO REPORTS
卷 21, 期 9, 页码 -出版社
WILEY
DOI: 10.15252/embr.202050863
关键词
duchenne muscular dystrophy; extracellular vesicles; HDAC inhibitors; microRNA; muscle regeneration
资金
- Association Francaise contre les Myopathies, Italian Ministry of Health [GR-2016-02362451]
- NIH/NIAMS [1R01AR076247-01]
- NIH/NIGMS [R01 GM134712-01]
- AFM postdoc fellowship
- EPIGEN F7
- DPP_Netherland postdoc fellowship
- DPP_Ita PhD fellowship
- MDA
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 expansionex 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.
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