Deciphering Skin Re-pigmentation Patterns in Vitiligo: An Update on the Cellular and Molecular Events Involved
Vitiligo is a common skin disorder characterized by the chronic and progressive loss of functional melanocytes, leading to well-defined depigmented macules and white patches on the skin. This condition affects 0.5% to 1% of the global population and can have a significant psychological impact, particularly in individuals with darker skin tones. Despite advancements in understanding the disease, the treatment of vitiligo remains challenging due to the unpredictable responses of patients to existing therapeutic regimens. This review aims to provide an updated understanding of the cellular and molecular mechanisms involved in skin re-pigmentation in vitiligo, focusing on the latest research and potential therapeutic strategies.
The clinical challenge in treating vitiligo lies in the variability of re-pigmentation outcomes. Current treatment strategies aim to arrest disease progression during the active stage and stimulate re-pigmentation during the inactive stage. Re-pigmentation is thought to involve a regenerative process where existing viable melanocyte precursors and/or melanocyte stem cells are recruited from the perilesional margins and/or unaffected hair follicles to repopulate the achromic skin. Interestingly, re-pigmentation in some areas can occur simultaneously with active depigmentation in other areas of the same patient, a phenomenon attributed to the presence of melanocyte-specific resident memory T cells in lesional skin tissues.
Ultraviolet B (UVB)-based phototherapy has been clinically proven to be effective in inducing re-pigmentation in vitiligo patients. Various re-pigmentation patterns, such as perifollicular, marginal, diffuse, and combined patterns, have been observed following UVB phototherapy. These patterns depend on the available source of melanocyte precursors or stem cells in the epidermis or hair follicles. For instance, the perifollicular re-pigmentation pattern is the most frequent, indicating that hair follicles serve as the primary melanocyte reservoir for this pattern. Patients with depigmented skin and pigmented hair typically develop a perifollicular re-pigmentation pattern after UVB phototherapy, whereas those with white hair (leukotrichia) show poor responses.
The bulge region of hair follicles is a relatively safe niche that houses melanocyte stem cells alongside keratinocyte stem cells. This region is part of the outer root sheath (ORS) and is considered an immune-privileged site, protected from immunologic inflammation. Keratinocytes in the bulge region secrete high levels of transforming growth factor-beta 1 (TGF-β1), which maintains melanocyte stem cells in a quiescent state by down-regulating the function of microphthalmia-associated transcription factor (MITF). The niche-derived TGF-β1 also plays an immunosuppressive role in maintaining the immune-privileged microenvironment surrounding the bulge region.
The cellular events involved in the formation of the perifollicular re-pigmentation pattern include the activation of dormant melanocyte stem cells (Dct+/c-Kit−/TYR−) residing in the bulge region by narrow-band UVB (NB-UVB). Once activated, these stem cells mobilize to exit the bulge region into the supra-bulge region, where they differentiate into melanoblasts (Dct+/c-Kit+/TYR−), also known as transit-amplifying cells (TA cells). These melanoblasts migrate upward through the ORS to the lesional epidermis and eventually differentiate into functional melanocytes (Dct+/c-Kit+/TYR+). The reduced inhibition of TGF-β1 in the bulge region enhances the mobilization capacity of UVB, accelerating the perifollicular re-pigmentation process.
In addition to TGF-β1, alpha-melanocyte-stimulating hormone (α-MSH) derived from keratinocytes plays a crucial role in stimulating the proliferation and differentiation of melanocytes/melanoblasts in the re-pigmented lesional skin after UVB exposure. A synthetic form of α-MSH, afamelanotide, combined with NB-UVB phototherapy, has shown superior and faster perifollicular re-pigmentation compared to NB-UVB monotherapy.
While the perifollicular re-pigmentation pattern has been extensively studied, less attention has been paid to the marginal re-pigmentation pattern. In this pattern, unaffected melanocytes bordering the depigmented skin are activated and migrate into the leukoderma areas. It is unclear whether differentiated melanocyte division occurs in vivo to contribute to this pattern. Mature melanocytes are generally considered terminally differentiated cells that have lost the ability to divide under normal physiological conditions. However, UVB irradiation may induce dedifferentiation, allowing these cells to regain the capacity to divide.
The interfollicular epidermis (IFE) may also harbor immature melanocytes that serve as the main cell source for marginal re-pigmentation. Studies using human scalp explant cultures have shown that follicular melanocytes can migrate to the epidermis, repopulating the skin epidermis. The TGF-β1-enriched bulge region of hair follicles is the primary niche for melanocyte stem cells, but a small fraction of melanocyte precursors may reach a bulge-like TGF-β1-enriched area in the epidermis, remaining in a quiescent state. UVB irradiation inhibits TGF-β1 production by keratinocytes, reducing its inhibitory effect on melanocyte growth and maturation, thereby improving marginal re-pigmentation.
The microenvironment favorable for vitiligo re-pigmentation involves the interplay of cytokines and chemokine networks. Reduced inhibition of TGF-β1 on melanocytes in the epidermis and hair follicles, increased transfer of pro-melanogenic growth factors from the dermis, and the formation of a CXCL12 chemokine-enriched microenvironment play crucial roles in the re-pigmentation process. UVB irradiation induces the release of heparan sulfate-binding growth factors, such as fibroblast growth factors and hepatocyte growth factor, from the dermal-epidermal junction (DEJ), facilitating melanocyte proliferation and melanogenesis.
Therapeutic skin trauma, such as dermabrasion, microneedling, ablative fractional CO2 lasers, and punch grafting, can also induce re-pigmentation in vitiligo patients resistant to conventional treatments. These interventions trigger a wound-healing process, mobilizing and activating melanocyte stem cells and precursors in the epidermis and hair follicles. The wounding-induced production of CXCL12 (SDF-1) by dermal fibroblasts and microvascular endothelial cells creates a concentration gradient that recruits CXCR4- or CXCR7-positive melanocytes or melanocyte precursors into the wound sites. Smaller punch grafts have been found to be more effective in achieving re-pigmentation, possibly due to a higher level of CXCL12 in the grafting sites.
In conclusion, vitiligo is a complex skin disorder with significant implications for patients’ quality of life. Current treatments, including phototherapy, topical corticosteroids, topical calcineurin inhibitors, and surgical procedures, have limited efficacies. Understanding the cellular and molecular mechanisms underlying skin re-pigmentation, such as the activation and mobilization of melanocyte stem cells, the role of TGF-β1 and α-MSH, and the formation of a supportive microenvironment, is crucial for developing novel therapeutic strategies. These advancements may accelerate cutaneous re-pigmentation and improve clinical outcomes in the treatment of vitiligo.
doi.org/10.1097/CM9.0000000000000794
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