HDACi treatment to correct communication between FAPs and Muscle Stem cells and counteract DMD pathology

External Seminars

favorite_border

calendar_month

10 Apr 11:30

HDACi treatment to correct communication between FAPs and Muscle Stem cells and counteract DMD pathology

place Monterotondo Campus “A. Buzzati Traverso” – Via E. Ramarini, 32 Monterotondo Scalo expand_more

Speaker: Martina Sandonà
IRCCS Fondazione Santa Lucia - Roma
Title: To Be Defined
Researcher Host: Alessio Torcinaro

Abstract

The functional exhaustion of muscle stem cells (MuSCs-satellite cells) contributes to Duchenne Muscular Dystrophy (DMD) progression by compromising the compensatory regeneration of diseased muscles. MuSCs activity is influenced

by functional interactions with cell types that compose their niche, including the muscle-resident mesenchymal stromal cells (MSCs) named fibro-adipogenic progenitors (FAPs) that regulate the regenerative ability of skeletal muscles in

physiological and pathological conditions. Since different groups have been shown that MSCs exert their beneficial effects through the release of Extracellular Vesicles (EVs), we investigated the role of FAP-derived EVs in DMD.

We revealed that dystrophic FAP-derived EVs support functional interactions with MuSCs and contribute to the beneficial effect of HDAC inhibitors (HDACi) on DMD muscles. FAP-derived EVs mediate microRNA transfer to MuSCs, and in

particular we demonstrated that exposure of dystrophic FAPs to HDAC inhibitors (HDACi) increases the intra-EV levels of a subset of microRNAs (miRs), which cooperatively target biological processes of therapeutic interest, including

regeneration, fibrosis and inflammation. In detail, increased levels of miR206 in EVs released from FAPs of muscles from DMD patients or dystrophic mdx mice exposed to HDACi correlated with improvement of key histological

parameters, such as compensatory regeneration and inhibition of fibrosis. Moreover, we observed that EVs from HDACitreated dystrophic FAPs stimulated MuSC activation and expansion ex vivo, and promoted regeneration, while inhibiting

fibrosis and inflammation of dystrophic muscles, upon intramuscular transplantation, in vivo. These data reveal a potential for the pharmacological modulation of FAP-derived EV’s content as novel cell-free strategy for local therapeutic

interventions in muscular diseases.