Non-genetic regulation of Cripto micro-heterogeneity secures satellite cell adaptive response to the regenerative microenvironment

Skeletal muscle repair relies on heterogeneous population of Satellite cells (SCs). The mechanisms that preserve SC population diversity are still unknown. Here we investigated the emerging role of non-genetic micro-heterogeneity, i.e., intrinsic cell-to cell variability of a population, in this process. We demonstrate that micro-heterogeneity of the membrane protein Cripto in activated satellite cells (ASCs) identifies metastable cell states that allow a rapid response of the population to environmental changes. Mechanistically, Cripto micro-heterogeneity is generated and maintained through a process of intracellular trafficking coupled with active shedding of Cripto protein from the plasma membrane. Irreversible perturbation of Cripto micro-heterogeneity alters the balance between proliferation, self-renewal and myogenic commitment of ASCs, resulting in increased self-renewal in vivo. Our findings reveal that Cripto micro-heterogeneity regulates the adaptative response of ASCs to microenvironmental changes, and provide new insights into the role of intrinsic heterogeneity in preserving stem cell population diversity during tissue repair.