Skeletal muscle represents up to 40% of the total body mass, making this tissue one of the most important organ systems. One major characteristic of skeletal muscle is its capacity to regenerate after injury. A heterogeneous population of muscle stem cells (MuSC), known as satellite cells, are essential to the regenerative process. Whereas relatively minor muscle injuries, such as strains, can heal completely without intervention, severe muscle injuries (laceration or secondary to disease such as Duchenne muscular dystrophy), typically result in the formation of fibrotic tissue that impairs muscle function. Although stem cell-based therapy emerged as a promising therapeutic target for muscle repair, progress in the field awaits a better definition of the type of cells to be used and how to improve their myogenic capacities in diseased muscles.

This Privat Docent thesis presents five of my studies that explore the therapeutic potential of myogenic precursor cells transplantation for muscle repair. We developed a novel pre-clinical model, in pig, for designing more efficient strategies of myoblast transplantation in patients. We also assessed the fate of human primary myoblasts after injection in immunodeficient mice. However, we identified a massive and early donor cell death post injection which limits the benefit of such therapeutic approach so far. We then determined strategies to improve myoblast survival after transplantation. We showed that ex-vivo gene transfer of the protective gene, heme oxygenase- 1 (HO-1), increases by five-fold porcine myoblast survival. We also demonstrated that low molecular weight dextran sulfate acts as a human myoblast protectant in vitro and is able in vivo, to prevent early human myoblasts cell death. Nevertheless, the overall efficiencies of these strategies remain unsatisfactory for possible therapeutic applications. A wealth of evidence indicates that freshly isolated MuSC, grown in conventional culture conditions ex vivo, are quickly activated out of quiescence, which correlate with a diminution of their regenerative potential. We demonstrated that human muscle reserve cells (MuRC), generated in vitro, are quiescent MuSC with properties required for their use in cell therapy i.e., they survive, they repair damaged myofibers and they generate new MuSC in vivo. We further show that MuRC-derived myoblasts display powerful immunosuppressive property in vitro. Finally, I present recent data on the characterization and functionality of human MuRC subpopulations (Pax7High and a Pax7Low) and discuss their specific features in the context of stem cell-based therapy for skeletal muscle diseases.