Regulatory mechanisms governing epidermal stem cell function during development and homeostasis

Abstract

Cell divisions and cell-fate decisions require stringent regulation for proper tissue development and homeostasis. The mammalian epidermis is a highly organized tissue structure that is sustained by epidermal stem cells (ESCs) that balance self-renewal and cell-fate decisions to establish a protective barrier, while replacing dying cells during homeostasis and in response to injury. Extensive work over past decades has provided insights into the regulatory mechanisms that control ESC specification, self-renewal and maintenance during different stages of the lifetime of an organism. In this Review, we discuss recent findings that have furthered our understanding of key regulatory features that allow ESCs to establish a functional barrier during development and to maintain tissue homeostasis in adults.

Keywords: Development; Epidermis; Homeostasis; Skin; Stem cells.

Fig. 1.

Epidermal stratification during development. Mammalian epidermal development is a multistage process consisting of cell fate specification, commitment, differentiation and stratification. The epidermis originates from a single embryonic ectoderm layer at embryonic day (E) 8.5. Upon epidermal fate commitment at E9.5, the surface ectoderm becomes the epidermal basal layer. Epidermal stratification begins at E14.5, when the basal layer gives rise to the intermediate layer, which eventually differentiates upward to establish a stratified epidermis. By birth, postnatal day (P) 0, the epidermis is fully formed with a single basal layer and differentiated suprabasal layers that consist of the spinous, granular and stratum corneum layers.

Fig. 2.

Oriented cell division during epidermal development. (A) Epidermal development is driven by oriented cell divisions. Divisions parallel to the basement membrane are called symmetric cell divisions (SCDs), which result in the formation of two basal cells. Divisions perpendicular to the basement membrane are called asymmetric cell divisions (ACDs), which give rise to one basal cell and one suprabasal cell that fuel epidermal stratification. (B) Schematic of the molecular machinery located at the apical cortex of a basal cell undergoing ACD. Par complex proteins and atypical protein kinase C (aPKC) localizes to the apical membrane of the cell. Par3 binds to inscuteable (Insc), which in turn recruits G-protein-signaling modulator 2 (LGN) to the apical cortex of the cell. Once anchored, LGN recruits nuclear mitotic apparatus protein 1 (NuMa), a microtubule-binding protein. NuMa directs the mitotic spindle through dynein. Together, this complex orients the mitotic spindle perpendicular to the basement membrane, aiding ACD.

Fig. 3.

Cell-proliferation models of adult epidermal stem cells during homeostasis. Several lineage-tracing experiments in the adult interfollicular epidermis (IFE) have led to conflicting models of epidermal stem cell (ESC) proliferation during homeostasis. (A) The single progenitor (SP) model states that each stem cell (SC) has an equal potential of self-renewal or differentiation, and these cell-fate decisions are stochastic. Each basal SC can proliferate to give rise to either two SCs, two differentiated cells or one SC and one differentiated cell. (B) The SC-CP model proposes a hierarchy of rare slow-cycling SCs, which divide to give rise to SCs or committed progenitor (CP) cells. The CP cells are a rapidly dividing pool of cells that are biased towards differentiation, hence establishing a scenario where SCs have to continually undergo proliferation to fuel cells required to maintain tissue homeostasis. (C) The 2×SC model proposes the IFE is composed of two populations of SCs: one fast cycling and one slow cycling. Each population of SCs make stochastic fate choices, as stated in A. The 2×SC model postulates that skin regions with fast-cycling SCs would have faster regeneration rates compared with the regions with slow-cycling SCs.