Ricerc@Sapienza

Duchenne muscular dystrophy (DMD) is the most severe neuromuscular dystrophy caused by mutations in the dystrophin gene that cause a total loss of the protein. Its absence involved an alteration of the skeletal muscles integrity. Unfortunately, there is not a cure for DMD but only treatments focused on an improvement of DMD patients¿ lifespan. Among them our group revealed the therapeutic potential of HDAC inhibitors. Of relevance, pre-clinical studies carried out in our group on the use of Givinostat to treat degeneration in the mouse model of DMD mdx-mice have led, for the first time, an HDACi to enter phase III clinical trial on DMD boys. In the last years, the enormous potential of Extracellular Vesicles (EVs) as cell-free treatment in regenerative medicine has been highlighted. We have recently described in dystrophic environment, the role of EVs in the functional communication between fibroadipogenic progenitors (FAPs) and muscle stem cells (MuSCs) and moreover, we have defined the ability of HDACi treatment to generate pro-regenerative EVs changing their miRNAs content. Starting from these results, we will deepen the FAPs-derived EVs characterization upon HDACi treatment focusing our attention on the changes in EVs protein content. We have performed a proteomic analysis showing a change in the protein expression profile of EVs-TSA. In this analysis the most up-regulated protein in EV-TSA is ItgB1 which is necessary for the maintenance of MuSCs quiescence in homeostasis, and drive MuSCs proliferation and self-renewal during muscle regeneration. This proposal aims to deeply investigate the role of ItgB1 transported by the FAPs-EVs to MuSCs into the determination of polarity and fate of MuSCs. We will evaluate the crosstalk between ItgB1 and FGF2, necessary to make MuSCs responsive to FGF signalling itself. The proposed study determining the role of ItgB1 in FAPs-EVs will lay the foundation for a new cell-free therapeutic strategy for DMD based on EVs.