Abstract Adult skin interfollicular epidermis (IFE) renewal is currently described by simple models of relatively homogenous basal stem/progenitor cells. However, long-term IFE renewal is likely orchestrated by the physiological demands of a complex tissue architecture comprising multiple levels of heterogeneity. We began to elucidate the cellular and molecular organization of two spatially distinct IFE domains, their physiological relevance, and the relationship between mouse and human skin. We demonstrate that molecular and cellular states of mouse tail basal microdomains (scales and inter-scales) recapitulate human skin IFE spatial organization in rete ridges and inter-ridges. We begin to uncover a physiological relevance for the skin spatial domains: adaptation to differential UV exposure. We identify multiple IFE populations with distinct behavior in clonal analysis and describe the first in vivo epidermal transit-amplifying (TA) cell. The later uniquely displays a maturation-dependent behavior with a timed-transition from an amplification phase to an extinction phase. This opens-up a new road for investigating molecular mechanisms of timed transitions from a ‘young’ to a ‘mature’ cell state. Using mouse genetics, we develop new tools to label and characterize IFE domains that are most UV exposed and examine in depth: (1) IFE spatial heterogeneity and domain organization in skin and its physiological significance; and (2) the heterogeneity of IFE stem/TA population behavior in skin, how this relates to regeneration capacity of spatial domains, and what are the mechanisms of cell fate transition from a young to a mature TA cell state, and from a stem to a TA cell. We propose that the extraordinary IFE complexity of basal cell states, multiple stem/TA cell populations, and spatial organization may explain the unusual robustness of skin homeostasis in response to constant environmental challenges.

Epidermal stem/progenitor cells of the adult skin are highly active and their response to normal and injury-generated signals is essential for organismal survival. Although it is a rapidly developing area of research, the heterogeneity, hierarchical lineage relationship, and the spatial distribution of diverse epidermal stem/progenitor cell populations in the mouse and human skin are poorly understood. Our laboratory has identified heterogeneity of the basal skin cells, containing stem/progenitor cells, and suggested a spatial patterning of distinct stem cell distribution that has the potential to advance our understanding in the area of human skin regeneration and wound healing.