Development and homeostasis of the skin epidermis

Abstract

The skin epidermis is a stratified epithelium that forms a barrier that protects animals from dehydration, mechanical stress, and infections. The epidermis encompasses different appendages, such as the hair follicle (HF), the sebaceous gland (SG), the sweat gland, and the touch dome, that are essential for thermoregulation, sensing the environment, and influencing social behavior. The epidermis undergoes a constant turnover and distinct stem cells (SCs) are responsible for the homeostasis of the different epidermal compartments. Deregulation of the signaling pathways controlling the balance between renewal and differentiation often leads to cancer formation.

Figure 1.

Skin morphogenesis and generation of epidermal cell lineages. During embryonic development the single-layered epidermis stratifies, resulting in layers of differentiated cells forming the mature epidermis and its appendages.

Figure 2.

Different types of SCs regulate epidermal homeostasis. Lineage-tracing analysis provided evidence for the contribution of each type of SC of the epidermis during normal homeostasis. (Middle boxed image reproduced, with permission, from Snippert et al. 2010 © Science.)

Figure 3.

Multipotency of bulge SCs during wound healing. Upon IFE wounding, HF bulge SCs migrate to the site of wounding and contribute to the regeneration of IFE. (Bottom images reproduced, with permission, from Tumbar et al. 2004, © AAAS.)

Figure 4.

Mechanisms ensuring genomic integrity in skin stem cells. Upon DNA damage, hair follicle bulge stem cells initiate the DNA damage response pathway, but because of higher levels of antiapoptotic Bcl-2 and DNA-PK (red arrows), they exhibit lower DNA damage–induced cell death, accelerated DNA repair, faster attenuation of p53 stabilization, and inhibition of apoptosis.

Figure 5.

Cells at the origin of the most common types of skin cancer. Activation of Hedgehog signaling in different cellular compartments of the epidermis using mice conditionally expressing constitutively active Smoothened mutant (SmoM2) showed that BCC does not arise by hair follicle stem cells as previously believed, but from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. Likewise, using the same approach and mice conditionally expressing a constitutively active KRas mutant (G12D), it was shown that squamous tumors can be generated by both interfollicular epidermis and hair follicle stem cells, but not their immediate progeny, whereas additional mutations have to occur to progress to the malignant state.

Figure 6.

Clinical use of skin stem cells. Autologous keratinocytes from skin biopsies can be cultured in vitro to generate skin sheets that will be used in patients with severe burns or, upon genetic manipulation, in patients with genetic skin disorders. (Portions reproduced, with permission, from Mavilio et al. 2006 © Nat Med.)