Trends in Regenerative Medicine: Repigmentation in Vitiligo Through Melanocyte Stem Cell Mobilization

Abstract

Vitiligo is the most frequent human pigmentary disorder, characterized by progressive autoimmune destruction of mature epidermal melanocytes. Of the current treatments offering partial and temporary relief, ultraviolet (UV) light is the most effective, coordinating an intricate network of keratinocyte and melanocyte factors that control numerous cellular and molecular signaling pathways. This UV-activated process is a classic example of regenerative medicine, inducing functional melanocyte stem cell populations in the hair follicle to divide, migrate, and differentiate into mature melanocytes that regenerate the epidermis through a complex process involving melanocytes and other cell lineages in the skin. Using an in-depth correlative analysis of multiple experimental and clinical data sets, we generated a modern molecular research platform that can be used as a working model for further research of vitiligo repigmentation. Our analysis emphasizes the active participation of defined molecular pathways that regulate the balance between stemness and differentiation states of melanocytes and keratinocytes: p53 and its downstream effectors controlling melanogenesis; Wnt/β-catenin with proliferative, migratory, and differentiation roles in different pigmentation systems; integrins, cadherins, tetraspanins, and metalloproteinases, with promigratory effects on melanocytes; TGF-β and its effector PAX3, which control differentiation. Our long-term goal is to design pharmacological compounds that can specifically activate melanocyte precursors in the hair follicle in order to obtain faster, better, and durable repigmentation.

Harnessing the Power of Regenerative Therapy for Vitiligo and Alopecia Areata

“…The regenerative properties of the HF bulge and bulb may play a role in reversing AA (Sequeira and Nicolas, 2012), whereas the success of vitiligo repigmentation is dictated by the presence of an intact HF bulge stem cell reservoir with melanocyte precursors able to proliferate, migrate, and differentiate (Goldstein et al, 2015). In both conditions, the regeneration process is regulated by coordinated signaling between melanocytes and keratinocytes, which are in a tight anatomical and functional relationship, along with interactions with other skin cells, such as fibroblasts and adipocytes (Birlea et al, 2017;Hsu et al, 2014).…”

“…Several signaling pathways involved in the maintenance, proliferation, and differentiation of melanocyte precursors are clearly implicated in the vitiligo repigmentation process: Wnt/b-catenin; alpha-melanocyte-stimulating hormone (a-MSH)/melanocortin 1 receptor; TGF-b; and paracrine/growth factors such as stem cell factor, endothelin-1, and bFGF (Birlea et al, 2017). These pathways converge to activate microphthalmia-associated transcription factor and transcription of its downstream melanogenic enzymes (Figure 2a).…”

Involvement of non‐melanocytic skin cells in vitiligo

“…Interestingly, Wnt/β-catenin pathway, which is involved in melanocyte differentiation and melanocyte stem cells mobilization, is deregulated in vitiligo lesions, [48,49] suggesting a relevant role of Wnt transduction pathway in non-physiological hypopigmentations. [51,52] Lesional skin is also characterized by upregulation of stress-induced negative regulators of the Wnt signalling, including p53. Defects in Wnt/β-catenin pathway, especially impaired activation of related intracellular signalling by oxidative stress, can also be responsible for a reduced differentiation of resident pre-melanocytes and dermal stem cells.…”

“…[54] Consequently, due to the association with inflammation, cellular stress and senescence and the modulation of DKK1 expression, or of the downstream Wnt signalling, represent a possible therapeutic target for vitiligo. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] Despite senescence is usually reported as a uniform phenotype with increased production of growth factors, it appears evident that in skin fibroblast, senescence-like phenotype sustains a wide range of acquired pathological alteration including cancer [57,58] hypo-and hyperpigmentation [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] suggesting that other specificity resides in the microenvironment or pathological context. Senescence in dermal fibroblasts can deregulate growth factors like basic fibroblasts (bFGF) and cytokines, leading to loss of melanocyte.…”

Mouse Model for Human Vitiligo

“…5A; Falabella, 2009). As a result, melanocytes can be regenerated from the hair follicles in an active process known as perifollicular repigmentation (Birlea, Costin, Roop, & Norris, 2017;Cui, Shen, & Wang, 1991). This occurs when the melanocyte precursors in the hair follicle bulge, proliferate, migrate, and differentiate to replenish the lost epidermal melanocytes.…”