Deciphering Skin Re-pigmentation Patterns in Vitiligo: An Update on the Cellular and Molecular Events Involved

Introduction

Vitiligo is a common skin disorder that affects 0.5% to 1% of the global population. It is characterized by well-defined depigmented macules and white patches on the skin, resulting from the chronic and progressive loss of functional melanocytes from the epidermis and/or hair follicles. This can have a significant psychological impact on patients, especially those with darker skin. While autoimmune-mediated cell death is widely accepted as the leading cause of melanocyte disappearance in most cases of vitiligo, the molecular mechanisms triggering melanocyte-specific immune responses remain unclear.

Current treatment of vitiligo is challenging due to variable patient responses to existing therapeutic regimens. Treatment strategies aim to arrest disease progression in the active stage and stimulate re-pigmentation in the inactive stage. Re-pigmentation is thought to involve a regenerative process where viable melanocyte precursors or stem cells are recruited to repopulate the achromic skin. However, re-pigmentation in some areas can parallel active depigmentation in others, which may be related to the presence of melanocyte-specific resident memory T cells in lesional skin tissues.

Ultraviolet B (UVB)-based phototherapy has been proven effective in inducing re-pigmentation, with various re-pigmentation patterns observed depending on the source of melanocyte precursors or stem cells. More recent studies have also explored the use of therapeutic skin trauma, such as dermabrasion, micro-needling, ablative fractional CO2 lasers, and punch grafting, as effective treatment options for difficult-to-treat areas. This article reviews the cellular and molecular mechanisms underlying re-pigmentation induced by UVB irradiation or therapeutic skin trauma, aiming to provide insights for developing novel therapeutic strategies.

Formation and Regulation of the Perifollicular Re-pigmentation Pattern

The perifollicular re-pigmentation pattern is the most frequent in human vitiligo, indicating that hair follicles are the main melanocyte reservoir for this pattern. Clinical evidence shows that vitiligo patients with leukoderma and pigmented hair typically develop a perifollicular re-pigmentation pattern after UVB phototherapy, while those with leukoderma and leukotrichia have poor responses.

The bulge region in hair follicles is a relatively safe niche that houses melanocyte stem cells. 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 via the down-regulated function of microphthalmia-associated transcription factor (MITF). UVB irradiation can activate dormant melanocyte stem cells in the bulge region, which then grow and differentiate into melanoblasts and eventually migrate to the lesional epidermis to differentiate into functional melanocytes.

Moreover, α-melanocyte-stimulating hormone (α-MSH) derived from keratinocytes is a main hormonal signal that stimulates the proliferation and differentiation of melanocytes/melanoblasts in the re-pigmented lesional skin after UVB exposures. A recent study demonstrated that afamelanotide, a synthetic form of α-MSH, in combination with NB-UVB phototherapy resulted in superior and faster perifollicular re-pigmentation compared to NB-UVB monotherapy.

Formation and Regulation of the Marginal Re-pigmentation Pattern

The marginal re-pigmentation pattern involves the activation of unaffected melanocytes bordering the depigmented skin, allowing them to migrate into the leukoderma areas. While mature melanocytes are generally viewed as terminally differentiated cells, there may be a population of immature melanocytes in normal human epidermal tissue that serves as the main cell source for marginal re-pigmentation.

Studies have shown that human follicular melanocytes have the ability to repopulate in the skin epidermis. Evidence also supports the presence of a bulge-like TGF-β1-enriched area in human epidermis, which may maintain the undifferentiated state of melanocytes. Suppression of TGF-β1 production by keratinocytes induced by UVB irradiation can decrease the inhibition of TGF-β1 on melanocyte growth and maturation, thereby improving marginal re-pigmentation.

Micro-environment Favorable for Vitiligo Re-pigmentation

In addition to the mobilization and activation of melanocytes and/or stem cells, re-pigmentation also depends on a favorable micro-environment. The mutual interactions of cytokines and chemokine networks in the treated skin play crucial roles.

Reduced Inhibition of TGF-β1 on Melanocytes Elicited by UVB

Micro-RNA (miR)-203, an epidermal-specific miRNA, is highly expressed in differentiated suprabasal keratinocytes. It post-transcriptionally represses the expression of p63 and c-Jun genes, which are involved in regulating TGF-β1 gene transcription. UVB irradiation can increase the expression of c-Jun and decrease the autocrine production of TGF-β1, suggesting new therapeutic approaches to down-regulate TGF-β1 expression and awaken dormant melanocytes.

Increased Transfer of Pro-melanogenic Growth Factors from the Dermis Induced by UVB

The dermal-epidermal junction (DEJ) is a dynamic interface structure. Perlecan, a heparan sulfate proteoglycan, is a key structural constituent of basement membranes and a storage reservoir of heparan sulfate-binding growth factors. Heparanase-induced degradation of heparan sulfate can increase the diffusion of pro-melanogenic growth factors, facilitating melanocyte proliferation and melanogenesis.

CXCL12 Chemokine-enriched Micro-environment Induced by Therapeutic Skin Trauma

Therapeutic skin trauma, such as dermabrasion, micro-needling, ablative fractional CO2 lasers, and punch grafting, can trigger a wound-healing process that mobilizes and activates melanocyte stem cells and precursors. CXCL12 (SDF-1) is up-regulated upon skin wounding and may form a concentration gradient to recruit CXCR4- or CXCR7-positive melanocytes or precursors. The injury and healing process may create an environment favorable for melanocyte stimulation and activation.

Conclusions

Vitiligo has a significant impact on patients’ quality of life. Current treatments have limited efficacies, and complete re-pigmentation may take months or years. Understanding the cellular and molecular mechanisms underlying skin re-pigmentation can help develop novel therapeutic strategies to accelerate cutaneous re-pigmentation and improve clinical outcomes. Further research is needed to explore the role of various factors and develop more effective treatments.

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