The Satellite Cell Niche Regulates the Balance between Myoblast Differentiation and Self-Renewal via p53

Satellite cells are adult muscle stem cells residing in a specialized niche that regulates their homeostasis. How niche-generated signals integrate to regulate gene expression in satellite cell-derived myoblasts is poorly understood. We undertook an unbiased approach to study the effect of the satellite cell niche on satellite cell-derived myoblast transcriptional regulation and identified the tumor suppressor p53 as a key player in the regulation of myoblast quiescence. After activation and proliferation, a subpopulation of myoblasts cultured in the presence of the niche upregulates p53 and fails to differentiate. When satellite cell self-renewal is modeled ex vivo in a reserve cell assay, myoblasts treated with Nutlin-3, which increases p53 levels in the cell, fail to differentiate and instead become quiescent. Since both these Nutlin-3 effects are rescued by small interfering RNA-mediated p53 knockdown, we conclude that a tight control of p53 levels in myoblasts regulates the balance between differentiation and return to quiescence. In this article, Pisconti et al. use an unbiased approach to show that the transcriptional program that drives myoblast cell fate transitions is directly regulated by the nature of the surrounding niche. The authors identify p53 as a niche-induced transcriptional regulator that increases in a subset of myoblasts upon cell-cycle exit, promoting quiescence at the expense of differentiation.