More than one way to skin .

Abstract

Epithelial stem cells in the skin are specified during development and are governed by epithelial-mesenchymal interactions to differentially adopt the cell fates that enable them to form the epidermis, hair follicle, and sebaceous gland. In the adult, each of three epithelial lineages maintains their own stem cell population for self-renewal and normal tissue homeostasis. However, in response to injury, at least some of these stem cell niches can be mobilized to repair an epithelial tissue whose resident stem cells have been damaged. How do these stem cell populations respond to multiple signaling networks, activate migration, and proliferation, and differentiate along a specific lineage? Recent clues add new pieces to this multidimensional puzzle. Understanding how these stem cells maintain normal homeostasis and wound repair in the skin is particularly important, as these mechanisms, when defective, lead to skin tissue diseases including cancers.

Figure 1.

Epithelial SC compartments in the skin. The epidermis contains a population of epidermal SCs (green) that reside in the basal layer (BL). In models where a small number of SCs and a large number of TA cells (red) reside within the basal layer, SCs are proposed to express elevated levels of β1 and α6 integrins and differentiate by delamination and upward movement to form the spinous layer (Sp), the granular layer (Gr), and the stratum corneum (StC). Recent findings suggest that by virtue of their ability to undergo asymmetric divisions, many if not all basal cells may have the capacity for self-renewal and epidermal stratification and differentiation. The SG contains a small number of progenitors that express the transcriptional repressor Blimp1 and reside near or at the base of the SG. SG progenitors produce proliferative progeny that differentiate into the lipid-filled sebocytes that signify the gland. The HF SCs reside in the bulge compartment below the SG. HF SCs are slow-cycling and express the cell surface molecules CD34 and VdR, as well as the transcription factors, TCF3, Sox9, Lhx2, and NFATc1. Bulge cells generate cells of the ORS, which are thought to fuel the highly proliferative matrix cells that are adjacent to the mesenchymal DP. After spurts of rapid proliferation, matrix cells differentiate to form the hair channel, the IRS, and the HS.

Figure 2.

Heterogeneity in the basal epidermal layer. Expression of β1 integrin and acetylated histone H4 (AcH4) are differentially expressed in human epidermis. In β1 integrin-high cells, acetylated histone H4 levels are reduced, suggesting that chromatin remodeling might play a role in the regulation of SCs within the epidermis. (Images courtesy of F. Watt) (Frye et al. 2007).

Figure 3.

The molecular mechanisms that control epithelial SC proliferation and differentiation in the skin. Epidermal SCs produce three differentiated cell types: the spinous cells, the granular cells, and the stratum corneum. The proliferation of epidermal SCs is regulated positively by β1 integrin and TGFα, and negatively (−) by TGFβ signaling. In addition, the transcription factors c-Myc and p63 control epidermal proliferation. Notch signaling and the transcription factors PPARα, AP2α/γ, and C/EBPα/β control the differentiation of epidermal cells. The HF SCs in the bulge region produce multiple progenitor cells in the ORS/HG and the matrix, which ultimately produce two differentiated lineages: the HS and the IRS. The proliferation of the bulge cells is controlled negatively (−) by BMP signaling and the transcription factors NFATc1 and P-TEN, and positively (+) by Wnt signaling. Differentiation of the IRS is controlled by Notch and BMP signaling and the transcription factors CDP and GATA-3. HS differentiation is controlled by Wnt signaling and its downstream transcription factor Lef1. Matrix (Mx) cells are controlled by Msx1/2, Ovo1, Foxn1, and Shh. The unipotent SG SCs are regulated negatively by the transcription factor Blimp1 and Wnt signaling, and positively by c-Myc and hedgehog signaling. The differentiation of sebocytes is thought to be directed by PPARγ expression.

Figure 4.

Lineage relationships in the HF. (Left panels) The DNA LRCs of the bulge can be marked by a 4-wk chase of histone H2B-GFP (green), regulated specifically in K5-positive keratinocytes in a tetracycline-controllable fashion (Tumbar et al. 2004). Once hair growth occurs, the bulge (Bu) remains GFP-high, and cells with diminishing GFP can be detected in the growing HG. Similar findings were obtained through genetic lineage tracing of bulge cells marked by expression of a Rosa26 lox-stop-lox lacZ transgene rendered active through K15-Cre-recombinase, active in the bulge cells and their progeny. (Reprinted by permission from MacMillan Publishers Ltd: Nat. Biotechnol.) (Morris et al. 2004). (Right panels) The matrix (Mx) cells of the HF (red arrowheads) can also be lineage-traced using regulatable lacZ expression. (Courtesy of E. Legue and J.F. Nicolas; reproduced with permission of the Company of Biologists) (Legue and Nicolas 2005). The isolated HFs shown here exhibit clonal contribution of Mx progeny to both the IRS and the HS.

Figure 5.

Evidence for a SG progenitor population. (Left panel) Skin sections are shown from mice in which retroviruses expressing lacZ were injected into the skin following wounding. The skin was then analyzed 70 d after injections. X-gal staining (blue) marks the SG and not the HF bulge (Bu) or the epidermis. (Reprinted by permission from MacMillan Publishers Ltd: EMBO J.) (Ghazizadeh and Taichman 2001). (Right panel) Skin sections of Rosa26-flox-stop-flox-YFP mice that also express Cre recombinase under the Blimp1 promoter. YFP becomes activated in all Blimp1-positive cells and their progeny, which here include the differentiated sebocytes that are PPARγ(+). (Reprinted from Cell, 126, with permission from Elsevier) (Horsley et al. 2006).