Regazzetti Claire, Joly Florence, Marty Carine, Rivier Michel, Mehul Bruno, Reiniche Pascale, Mounier Carine, Rival Yves, Piwnica David, Cavalié Marine, Chignon-Sicard Bérengère, Ballotti Robert, Voegel Johannes, Passeron Thierry
C3M, INSERM U1065, team 12, Nice, France.
Galderma R&D, Sophia-Antipolis, France.
J Invest Dermatol. 2015 Dec;135(12):3105-3114. doi: 10.1038/jid.2015.335. Epub 2015 Aug 31.
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.
白癜风影响着全球1%的人口。阻止疾病进展和使皮损皮肤复色是白癜风治疗挑战的两个方面。我们对白癜风患者的皮损、皮损周边和未脱色皮肤以及健康受试者的匹配皮肤进行了转录组分析。我们发现，与健康对照皮肤相比，白癜风未脱色皮肤和皮损周边皮肤中的CXCL10显著增加；然而，在脱色的白癜风皮肤中，CXCL10和其他免疫因子均未失调。有趣的是，参与黑素细胞分化的WNT通路在白癜风皮肤中发生了特异性改变。我们证明氧化应激会降低角质形成细胞和黑素细胞中WNT的表达/激活。我们建立了一个体外皮肤模型，并证实了在遭受氧化应激的人类皮肤中WNT通路的激活减少。最后，我们使用激活WNT通路的药物制剂，对白癜风患者的体外脱色皮肤进行治疗，并成功诱导驻留干细胞分化为前黑素细胞。我们的研究结果揭示了WNT激活减少在防止脱色白癜风皮肤中黑素细胞分化方面以前未被认识的作用。此外，这些结果支持进一步临床探索WNT激动剂以使白癜风皮损复色。
