HDAC inhibitors tune miRNAs in extracellular vesicles of dystrophic muscle-resident mesenchymal cells

Valentina Saccone, Martina Sandonà, Silvia Consalvi, Luca Tucciarone, Marco De Bardi, Manuel Scimeca, Daniela Francesca Angelini, Valentina Buffa, Adele D'Amico, Enrico Silvio Bertini, Sara Cazzaniga, Paolo Bettica, Marina Bouché, Antonella Bongiovanni, Pier Lorenzo Puri

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

5 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)1-19
Numero di pagine19
RivistaEMBO Reports
Volume21
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • HDAC inhibitors
  • duchenne muscular dystrophy
  • extracellular vesicles
  • microRNA
  • muscle regeneration

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