Homeostatic Epidermal Stem Cell Self-Renewal Is Driven by Local Differentiation

Maintenance of adult tissues depends on sustained activity of resident stem cell populations, but the mechanisms that regulate stem cell self-renewal during homeostasis remain largely unknown. Using an imaging and tracking approach that captures all epidermal stem cell activity in large regions of living mice, we show that self-renewal is locally coordinated with epidermal differentiation, with a lag time of 1 to 2 days. In both homeostasis and upon experimental perturbation, we find that differentiation of a single stem cell is followed by division of a direct neighbor, but not vice versa. Finally, we show that exit from the stem cell compartment is sufficient to drive neighboring stem cell self-renewal. Together, these findings establish that epidermal stem cell self-renewal is not the constitutive driver of homeostasis. Instead, it is precisely tuned to tissue demand and responds directly to neighbor cell differentiation. By capturing all stem cell activity in large regions of the mouse epidermis, Mesa et al. report that stem cell self-renewal is induced by the differentiation of neighbors. This study identifies the physiological factors that drive stem cell self-renewal, expanding the current understanding of epidermal homeostasis and regeneration.