Regulation of the skeletal muscle stem cell niche
Developmental & Stem Cell Biology, CNRS UMR 3738, Institut Pasteur, Paris.
The microenvironment is critical for the maintenance of stem cell populations, and it can be of cellular and non-cellular nature, including secreted growth factors and extracellular matrix (ECM) as well as intrinsic regulators. Skeletal muscle satellite (stem) cells are quiescent during homeostasis and they are mobilised to restore tissue function after muscle injury. Although certain signalling pathways that regulate quiescence have been identified, the mechanisms by which niche molecules regulate stem cell properties remain largely unknown. We have identified Notch signalling as a major regulator of the muscle stem cell niche. Specifically, Notch/RBPJ-bound regulatory elements are located adjacent to specific collagen genes in adult muscle satellite cells. These molecules are linked to the ECM and constitute putative niche components. Notably, 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 differentiation of satellite cells. Strikingly, COLV, but not collagen I and VI, specifically regulated quiescence through Calcitonin receptor mediated activity, therefore, a Notch/COLV signalling cascade cell-autonomously maintains the stem cell quiescent state, and raises the possibility of a similar reciprocal mechanism acting in diverse stem cell populations. This novel mechanism of stem cell niche regulation implicates a reciprocal mechanism were a mechanotransduction ECM protein acts as a signalling molecule for cell autonomous regulation of stem cell quiescence. Notch signalling also acts in an intrinsic manner to regulate a microRNA pathway to modulate cell migration and stem cell quiescence. These findings point to two distinct modulatory mechanisms for maintaining stem cell and niche stability.