LB1016 Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer

In the mammalian skin epidermis, it has long been unclear how molecularly heterogenous stem/progenitor cell populations fit into complete trajectory of epidermal differentiation. Here, we combine in vivo imaging with single-cell RNA sequencing to define early stages stem differentiation at molecular and behavioral level. We show that differentiation, from commitment exit layer, is a multi-day process wherein cells transit through gradual continuum transcriptional changes. By tracking regions over many days, find differentiation-committed remain capable dividing produce daughter fated further differentiate, demonstrating uncoupled cycle exit. These divisions occur as response local density changes, are not required part an obligate amplifying program but instead help buffer differentiating pool upon disruption barrier. Thus, distinct contributions multiple progenitor types, single continuous shaped by feedback environment fuels lifelong turnover epidermis.