Melanocyte dysfunctions: future and promise of stem cells

Abstract

Human melanocytes (MCs) and melanocyte stem cells (McSCs) are integral to skin pigmentation and appendage pigmentation, originating embryonically from neural crest cells. In adult skin, McSCs residing in the epidermis sustain the continuous regeneration of functional melanocytes, a process vital for skin homeostasis and repair. Advances in McSC research have unravelled their pivotal roles in combating disorders such as vitiligo, hair greying, impaired wound healing, and melanoma. Previous studies have significantly advanced our knowledge of the cellular and molecular characteristics of this unique stem cell population. However, a comprehensive understanding of their characteristics in melanocyte dysfunctions leading to conditions like vitiligo is still lacking. Dysfunction or depletion of McSCs is linked to these conditions, highlighting their significance in maintaining skin health. Cutting-edge technologies like single-cell RNA sequencing, spatial transcriptomics, gene editing, and whole-genome sequencing have deepened our understanding of McSC biology and their regulatory microenvironment. This review delves into the latest discoveries, offering a comprehensive perspective on McSCs and their therapeutic potential. By identifying specific molecular signals and crosstalk mechanisms, McSC research opens avenues for regenerative medicine applications, including skin repigmentation, tissue repair, and cancer treatment. The field's progression sets the stage for transformative breakthroughs in skin regeneration and broader regenerative therapies.

Keywords: Melanocyte stem cell; hair greying; homeostasis; melanoma; microenvironment.

Figure 1

A simplified diagram of melanin synthesis in melanocytes during melanogenesis. Tyrosine is transformed into melanin - a polymer composed of the pigments eumelanin (black-brown) and pheomelanin (yellow-red) - through the action of key enzymes including tyrosinase (TYR), tyrosine-related protein 1 (TYRP1), and tyrosine-related protein 2 (TYRP2).

Figure 2

A schematic illustration depicting the structure of the hair follicle and the behaviour of melanocyte stem cells (MSCs) and their progeny throughout the hair cycle. A. In early anagen, quiescent MSCs (represented as blue dots) located in the follicular bulge become activated, migrate down the outer root sheath (ORS), and differentiate into mature melanocytes (green dots) within the follicular bulb. B. During the catagen phase, mature melanocytes and transitional follicular cells undergo apoptosis, while quiescent MSCs remain in the bulge. C. In the telogen phase, MSCs stay dormant in both the bulge and the hair germ (HG) until the cycle restarts with a new anagen phase. APM: arrector pili muscle, BG: bulge, DP: dermal papilla, HFSCs: hair follicle stem cells, HS: hair shaft, IRS: inner root sheath, P: permanent portion, SG: sebaceous gland, T: transient portion. Adapted from Huang et al., 2024 [22].

Figure 3

Origin and development of melanocytes in mammals, melanocytes originate from neural crest cells (NCCs), with melanoblasts lineages emerging through the downregulation of transcription factors such as FOXD3 and NEUROG2 and/or SOX2 in progenitor cells. The melanocytic lineage maintains expression of SOX10, which subsequently triggers the activation of key melanogenic markers including MITF, DCT, and C-KIT. As melanoblasts migrate and colonize developing embryonic hair follicles, some differentiate into pigment-producing melanocytes responsible for colouring hair during the first hair cycle. Others downregulate MITF and become melanocyte stem cells (MSCs), which localize to the hair follicle bulge and secondary hair germ. These MSCs sustain the melanocyte population by generating transit-amplifying cells that proliferate and mature into functional melanocytes during each hair cycle. Additionally, Schwann cell progenitors - also derived from SOX10-expressing NCCs - can contribute to the pigmented cell population by repressing FOXD3. In the skin, neural crest-like progenitor cells also retain the capacity to differentiate into mature melanocytes (Adapted from Cui and Man, 2023) [27].