Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients

Abstract

Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions.

MicroRNA-211 Regulates Oxidative Phosphorylation and Energy Metabolism in Human Vitiligo

“…Transcriptomic analysis of HEM-l and PIG3V revealed similar changes in many of the immune, cell cycle, and pigmentation pathway genes shown to be differentially expressed in vitiliginous lesions (Dey-Rao and Sinha, 2016, Rashighi et al , 2014, Regazzetti et al , 2015). Our finding of highly significant downregulation of pigmentation genes downstream of MITF (a master regulator of melanogenesis, six-fold downregulated) A in PIG3V cells confirmed defects in melanin biosynthesis and pigmentation and provided confidence that the changes seen in vitro were representative of the clinical disease state.…”

Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease

“…In a recent study that examined a large number of vitiligo patients, serum levels of CXCL9 and CXCL10 correlated with disease activity, while only CXCL10 reflected disease severity (Wang et al , 2016), and another study reported low-level expression of CXCL10 in stable lesions (Regazzetti et al , 2015). Therefore, targeting both CXCL9 and CXCL10 may be important for treating active disease, whereas stable disease may be treated by blocking CXCL10 alone (Rashighi et al , 2014; Regazzetti et al , 2015; Wang et al , 2016). Future clinical studies will need to be conducted to determine the therapeutic potential for targeting CXCR3 ligand expression in keratinocytes as a treatment for vitiligo.…”

Critical appraisal of the oxidative stress pathway in vitiligo: a systematic review and meta‐analysis

“…However, in keratinocytes increased apoptosis and oxidative stress have also been found, indicating that the oxidative findings in vitiligo are not melanocyte specific . It is currently unclear whether epidermal oxidative stress is indeed the primary cause leading to the release of proinflammatory chemokines or if a generalized subtle skin inflammation may explain the findings on oxidative stress in non‐lesional vitiligo skin . Evidence for a small‐scale inflammation has indeed been found in non‐lesional vitiligo skin with more expression of chemokines (e.g.…”

“…CXCL10) and overexpressed innate immune markers (e.g. natural killer cell receptors KLCR4 and KLRG1) in normal‐appearing skin …”