Reciprocal signalling by Notch–Collagen V–CALCR retains muscle stem cells in their niche

Abstract

The microenvironment is critical for stem cell maintenance and can be of cellular and non-cellular composition, including secreted growth factors and extracellular matrix (ECM)1–3. Although Notch and other signalling pathways have been reported to regulate quiescence4–9, the composition and source of niche molecules remain largely unknown. Here, we show that adult muscle satellite (stem) cells produce ECM collagens to maintain quiescence cell-autonomously. By ChIP-sequencing we identified NOTCH/RBPJ-bound regulatory elements adjacent to specific collagen genes, whose expression is deregulated in Notch mutant mice. Moreover, we show that satellite cell produced collagen V (COLV) is a critical component of the quiescent niche, as conditional deletion of Col5a1 leads to anomalous cell cycle entry and gradual diminution of the stem cell pool. Notably, the interaction of COLV with satellite cells is mediated by CALCR, for which COLV acts as a surrogate local ligand. Strikingly, systemic administration of a calcitonin derivative is sufficient to rescue the quiescence and self-renewal defects scored in COLV null satellite cells. This study unveils a Notch/COLV/CALCR signalling cascade that cell-autonomously maintains the satellite cell quiescent state and raises the possibility of a similar reciprocal mechanism acting in diverse stem cell populations.