The cell microenvironment, which is critical for stem cell maintenance, contains both cellular and non-cellular components, including secreted growth factors and the extracellular matrix1,2,3. Although Notch and other signalling pathways have previously been reported to regulate quiescence of stem cells4,5,6,7,8,9, the composition and source of molecules that maintain the stem cell niche remain largely unknown. Here we show that adult muscle satellite (stem) cells in mice produce extracellular matrix collagens to maintain quiescence in a cell-autonomous manner. Using chromatin immunoprecipitation followed by sequencing, we identified NOTCH1/RBPJ-bound regulatory elements adjacent to specific collagen genes, the expression of which is deregulated in Notch-mutant mice. Moreover, we show that Collagen V (COLV) produced by satellite cells is a critical component of the quiescent niche, as depletion of COLV by conditional deletion of the Col5a1 gene 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 the Calcitonin receptor, for which COLV acts as a surrogate local ligand. Systemic administration of a calcitonin derivative is sufficient to rescue the quiescence and self-renewal defects found in COLV-null satellite cells. This study reveals a Notch–COLV–Calcitonin receptor signalling cascade that maintains satellite cells in a quiescent state in a cell-autonomous fashion, and raises the possibility that similar reciprocal mechanisms act in diverse stem cell populations.
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We thank H. Stunnenberg for the ChIP–seq and RNA sequencing data; D. Castro for the RBPJ ChIP protocol; D. Greenspan for the anti-a3-COLV antibody and Col5a3-knockout muscle samples; C. Moali for the SPR assay; F. Auradé and the Protein Core Facility, Institut Curie, for the production of CalcR proteins; K. Ding for the 7rh DDR1 inhibitor; F. Ruggiero for suggesting the on-cell enzyme-linking immunosorbent assay experiment; and the Cytometry platforms of Institut Pasteur and IMRB, Inserm U955, Creteil. F.R. was funded by the Association Française contre les Myopathies via TRANSLAMUSCLE (PROJECT 19507), Agence Nationale pour la Recherche grant Satnet (ANR-15-CE13-0011-01) and RHU CARMMA (ANR-15-RHUS-0003). S.T. was funded by Institut Pasteur, Centre National pour la Recherche Scientific and the Agence Nationale de la Recherche (Laboratoire d’Excellence Revive, Investissement d’Avenir; ANR-10-LABX- 73) and the European Research Council (Advanced Research Grant 332893). M.B.B. was funded by the Doctoral School grant and Fondation pour la Recherche Médicale.
Nature thanks I. Conboy, G. Kardon and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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npj Regenerative Medicine (2018)