A switch in cilia-mediated Hedgehog signaling controls muscle stem cell quiescence and cell cycle progression

Summary Tissue homeostasis requires a tight control of stem cells to maintain quiescence in normal conditions, and ensure a balance between progenitor cell production and the need to preserve a stem cell pool in repair conditions. Using ex-vivo and in-vivo genetic approaches, we provide evidence that primary cilium-mediated repressive Hedgehog (Hh) signalling is required to maintain skeletal muscle stem cells (MuSCs) in a quiescent state. De-repression and further activation of Hh signalling initiates MuSC entry and progression through the cell cycle, and controls self-renewal to ensure efficient repair of injured muscles. We propose a model whereby disassembly of primary cilia upon MuSC activation induces a switch in Hh signalling from a repressive to active state that controls exit from quiescence. Positive Hh response in bi-potential muscle progenitor cells regulates also cell cycle progression and drives MuSC self-renewal. These findings identify Hh signalling as a major regulator of MuSC activity. Highlights Cilia-containing quiescent MuSCs are Hh signalling suppressed MuSC activation coincides with a switch to active Hh signalling Smo mutation delays cell cycle entry and progression, and causes impaired self-renewal Ptch1 mutation promotes exit from quiescence, rapid cell cycle and increased self-renewal Graphical abstract