Delineating cilia-mediated signaling network in muscle stem cells – STEMCIL

Life-long skeletal muscle function relies on maintenance and regeneration of myofibers through a finely regulated process. It begins with activation of normally quiescent muscle stem cells (MuSCs) and proceeds with formation of proliferating MuSCs that either differentiate to repair injured myofibers or self-renew and return to quiescence to replenish the stem cell pool. MuSC loss/dysfunction inevitably result in muscle-wasting disorders, such as neuromuscular diseases, equaling poor quality of life, loss of independence and increased morbidity/mortality. Thus, a thorough understanding of the fundamental biological processes regulating MuSCs will warrant the success of stem cell-based regenerative therapies. We recently showed that MuSCs harbor a primary cilium that actively controls Hedgehog signaling to regulate their regenerative function. Interestingly, quiescent and proliferating MuSC-primary cilia do not contain the same of Hedgehog-related signaling molecules, suggesting that receptors and associated signaling effectors trafficking into primary cilia depend on MuSC state, i.e. quiescence/self-renewal or activation/proliferation, and act in primary cilia in a cell-context-dependent manner. Moreover, our preliminary data indicate that in mdx mice, a model of human Duchenne Muscular Dystrophy (DMD), where proliferating MuSC fate is impaired, mdx MuSCs exhibit abnormally elongated primary cilia. Together, these data support a model where the primary cilium coordinates MuSC signaling to regulate their quiescence/self-renewal and activation/proliferation and suggest that MuSC dysfunction in DMD could appear consecutively to the loss of primary cilia integrity. In this application, we propose different experimental approaches aiming at deciphering the signaling pathways mediated by the primary cilium in MuSCs in physiological and dystrophic contexts.