Skin pigmentation and its control: From ultraviolet radiation to stem cells

Abstract

In the light of substantial discoveries in epithelial and hair pigmentation pathophysiology, this review summarizes the current understanding of skin pigmentation mechanisms. Melanocytes are pigment-producing cells, and their key regulating transcription factor is the melanocyte-specific microphthalmia-associated transcription factor (m-MITF). Ultraviolet (UV) radiation is a unique modulator of skin pigmentation influencing tanning pathways. The delayed tanning pathway occurs as UVB produces keratinocyte DNA damage, causing p53-mediated expression of the pro-opiomelanocortin (POMC) gene that is processed to release α-melanocyte-stimulating hormone (α-MSH). α-MSH stimulates the melanocortin 1 receptor (MC1R) on melanocytes, leading to m-MITF expression and melanogenesis. POMC cleavage also releases β-endorphin, which creates a neuroendocrine pathway that promotes UV-seeking behaviours. Mutations along the tanning pathway can affect pigmentation and increase the risk of skin malignancies. MC1R variants have received considerable attention, yet the allele is highly polymorphic with varied phenotypes. Vitiligo presents with depigmented skin lesions due to autoimmune destruction of melanocytes. UVB phototherapy stimulates melanocyte stem cells in the hair bulge to undergo differentiation and upwards migration resulting in perifollicular repigmentation of vitiliginous lesions, which is under sophisticated signalling control. Melanocyte stem cells, normally quiescent, undergo cyclic activation/differentiation and downward migration with the hair cycle, providing pigment to hair follicles. Physiological hair greying results from progressive loss of melanocyte stem cells and can be accelerated by acute stress-induced, sympathetic driven hyperproliferation of the melanocyte stem cells. Ultimately, by reviewing the pathways governing epithelial and follicular pigmentation, numerous areas of future research and potential points of intervention are highlighted.

Keywords: MC1R; hair greying; melanocyte stem cells; perifollicular repigmentation; tanning.

Figure 1:

The delayed tanning pathway. UV radiation causes keratinocyte DNA damage and p53 expression. P53 expression leads to transcription of POMC. Processing of POMC produces α-MSH and β-endorphins. α-MSH binds MC1R on melanocytes which leads to the expression of MITF and resultant melanogenesis. As a byproduct of POMC cleavage, β-endorphins can influence tanning addiction.

Figure 2:

CRTC regulates the expression of MITF independent of CREB phosphorylation by PKA. CRTC can be sequestered in the cytoplasm via phosphorylation by salt inducible kinase (SIK). SIK inhibitors lead to increased un-phosphorylated CRTC, which can increase MITF expression and melanogenesis.

Figure 3:

Melanocyte stem cells are located in the hair bulge. Perifollicular re-pigmentation occurs as a portion of quiescent melanocyte stem cells and melanoblasts become activated and migrate to the supra bulge region. From the supra bulge region they undergo further differentiation and migration upwards along the outer root sheath and into the peripheral epidermis.