Epidermal stem cell diversity and quiescence

Abstract

Mammalian epidermis is maintained by self-renewal of stem cells and terminal differentiation of their progeny. New data reveal a diversity amongst stem cells that was previously unrecognized. Different stem cell populations have different locations and differ in whether they are quiescent or actively cycling. During normal epidermal homeostasis, each stem cell population feeds a restricted number of differentiated lineages. However, in response to injury or genetic manipulation the different pools of stem cells demonstrate multi-lineage differentiation ability. While it is well established that Wnt signalling promotes hair follicle (HF) differentiation, new observations suggest a role for EGF receptor signalling in promoting differentiation of interfollicular epidermis. NFATc1 maintains quiescence in the HF, while Lrig1 exerts the same function in the junctional zone. The stage is now set for exploring the relationship between the different epidermal stem cell populations and between quiescence and lineage selection.

Figure 1. Organization of adult mouse epidermis

1. The differentiated lineages of the interfollicular epidermis (IFE), sebaceous gland (SG) and hair follicle (HF) are shown. ORS, outer root sheath; IRS, inner root sheath.

2. In response to appropriate stimuli, stem cells (SC) in any region of the epidermis can give rise to any of the epidermal differentiated lineages. SCs are therefore represented as being interconvertible. Based on Owens and Watt (2003).

Figure 2. Different epidermal SC populations in adult mouse HF and junctional zone

Red: Lrig1 expressing cells of the junctional zone (Jensen et al, 2009). Blue: CD34 negative, α6 low cells of the upper isthmus (Jensen et al, 2008). MTS24 is expressed by both populations. Orange and green: CD34 positive, K15 positive cells of the bulge (Lyle et al, ; Trempus et al, 2003). The suprabasal, α6 low subpopulation is shown in pale green (Blanpain et al, 2004). Orange: Lgr5 expressing cells (Jaks et al, 2008). Label retaining cells are indicated by asterisks. The club hair shaft is shown in black within the bulge region.

Figure 3. Regulation of epidermal SC quiescence and lineage selection

All SCs may arise from a common population of embryonic SCs that reside in the developing HF (Lrig1, NFATc1 and Sox9 positive). In adult epidermis, Myc promotes proliferation of interfollicular epidermal and SG SCs. Quiescence is maintained by negative regulation of Myc by Lrig1 and Blimp1 in the IFE and SG, respectively. Lrig1 is a Myc target gene and Lrig1 expression reduces Myc activity. NFATc1 maintains quiescence of bulge SCs by negatively regulating CDK4.