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 homeostasis^1-5. Meanwhile, others posit a model in which stem cell differentiation occurs through an intermediate transit-amplifying-like progenitor state with strictly limited proliferative potential^6-10. Here, to determine the heterogeneity and pattern of cell fate, we performed intravital time-lapse imaging to track the fate of lineage-labelled cells in the skin interfollicular epidermis. Results from quantitative analyses of clonal dynamics support a two-compartment model of epidermal homeostasis, whereby basal cells are organized in a stem cell-transit-amplifying cell hierarchy. Critical to these conclusions was the discovery of 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 analyses of castrated mice revealed that male sex hormones promote stem cell differentiation and delamination. In summary, our study provides insight into the functional identity of the stem cell population and identifies sex-specific differences in the regulation of epidermal stem cells and transit-amplifying cell fate.