Abstract
SIGNIFICANCE: The skin interfollicular epidermis (IFE) is an organism's first line of defense against a harmful environment and physical damage. During homeostasis and wound repair, the IFE is rejuvenated constantly by IFE stem cells (SCs) that are capable of both proliferation and differentiation. However, the identity and behavior of IFE SCs remain controversial. RECENT ADVANCES: Two opposing theories exist regarding homeostasis of the IFE. On the basis of morphological and proliferative characteristics, one posits that the IFE is composed of a discrete epidermal proliferative unit comprised of ∼10 transit-amplifying (TA) cells and a centrally located SC in the basal layer. The other suggests that homeostasis of the IFE is maintained by a single progenitor population in the basal layer. A recent study has challenged these two apparently distinct models and demonstrated that the basal layer of the IFE contains both SCs and TA cells, which make distinct contributions to tissue homeostasis and repair. Moreover, phosphorylation levels of the transcription factor p63, the master regulator of the proliferative potential of epidermal SCs, can be used to distinguish self-renewing SCs from TA cells with more limited proliferative potential. CRITICAL ISSUES: As technologies advance, IFE SCs can be identified at a single-cell level. Refinements of their identification and characterization are critical, not only for SC biology but also for the development of novel clinical applications. FUTURE DIRECTIONS: Understanding the signaling pathways that control self-renewal and differentiation of IFE SCs will aid in developing novel cell-based therapeutics targeting degenerative epidermal diseases and wound repair.