Sexual dimorphism in epidermal stem cell dynamics

The epidermis is a stratified epithelium comprising proliferative basal cells and differentiated suprabasal cells that are continuously renewed throughout life. Conflicting theories have been proposed regarding the heterogeneity of the basal cell layer, with some studies proposing that all proliferative cells have self-renewal potential during homeostasis1–5 while others posit a model in which stem cell (SC) differentiation occurs through an intermediate transit-amplifying (TA)-like progenitor state with strictly limited proliferative potential6–10. To elucidate the heterogeneity and pattern of cell fate, we performed intravital timelapse imaging to track the fate of lineage-labelled cells in the skin interfollicular epidermis (IFE). Quantitative analysis of clonal dynamics supports a two-compartment model of epidermal homeostasis, with basal cells organized in a stem-TA cell hierarchy. Critical to these conclusions was the discovery of a sexual dimorphism in epidermal fate, with female mice showing a highly synchronized pattern of cell division, differentiation and delamination that contributes to accelerated wound healing. Single-cell RNA sequencing, transcriptional profiling, and clonal analysis following castration revealed that male sex hormones promote SC differentiation and delamination. As well as providing insight into the functional identity of the SC population, our study uncovers sex-specific differences in the regulation of epidermal stem and TA cell fate.