Development and Maintenance of Epidermal Stem Cells in Skin Adnexa

Abstract

The skin surface is modified by numerous appendages. These structures arise from epithelial stem cells (SCs) through the induction of epidermal placodes as a result of local signalling interplay with mesenchymal cells based on the Wnt-(Dkk4)-Eda-Shh cascade. Slight modifications of the cascade, with the participation of antagonistic signalling, decide whether multipotent epidermal SCs develop in interfollicular epidermis, scales, hair/feather follicles, nails or skin glands. This review describes the roles of epidermal SCs in the development of skin adnexa and interfollicular epidermis, as well as their maintenance. Each skin structure arises from distinct pools of epidermal SCs that are harboured in specific but different niches that control SC behaviour. Such relationships explain differences in marker and gene expression patterns between particular SC subsets. The activity of well-compartmentalized epidermal SCs is orchestrated with that of other skin cells not only along the hair cycle but also in the course of skin regeneration following injury. This review highlights several membrane markers, cytoplasmic proteins and transcription factors associated with epidermal SCs.

Keywords: epidermal placode; hair pigmentation; keratins; markers; signalling; skin adnexa; stem cell.

Figure 1

Periderm in embryonic epidermis. The periderm forms the outermost layer of embryonic skin that looks like a single superficial layer of flattened cells which functions as a permeability barrier. E12 mouse; staining with haematoxylin–eosin (A). After the appearance of an intermediate cell layer, the periderm becomes separated from the basal layer. Skin of a 14-week human embryo; anti-keratin 19 immunoperoxidase staining (B). Scale bar 50 μm.

Figure 2

Initial stages of hair follicle (HF) formation. Local proliferation of epidermal stem cells results in epidermal thickening, characterizing an epidermal placode. Basal columnar cells communicate actively with mesenchymal cells that cluster under the basement membrane. Skin of a 14-week human embryo, haematoxylin–eosin staining (A). In a 17-week human embryo, the epidermis becomes thicker, and hair buds invaginate deep into the dermis to form hair pegs. Intense keratin 19 immunostaining is specific for the basal layer of the epidermis; some keratin 19-positive cells persist in hair pegs and periderm (B). Scale bar 50 μm.

Figure 3

Formation of the nail. Nail proximal (PM) and distal matrix (DM) constitute a nail stem cell niche. In the dorsal side of a fingertip of a 14-week human embryo, a ventral proximal fold is in close association with PM; a nail bed (B) appears in continuation of the nail matrix (A). A transverse section of a distal tip of the little finger in a 17-week human embryo shows a curved course of PM, with overlying ventral proximal fold (VPF); distal phalanx (Ph; B); a detail of the association of PM and VPF in a longitudinal section (C). A schematic drawing of the arrangement of epithelial structures associated with an adult nail, with the distribution of some SC markers; eponychium (Ep), hyponychium (Hy; D). Scale bars 25 μm.

Figure 4

Heterogeneous stem cell populations residing in the epidermis. A schematic drawing represents interfollicular epidermis (IFE), sweat gland (SwG), sebaceous gland (SG), and characteristic morphologic parts of the hair follicle: infundibulum (In), isthmus (Is), upper bulge (UB), lower bulge (LB) and hair germ (G). Distinct stem cell populations can be characterized by specific markers. Modified from [41,43,44].