Altered laminin signaling destinates melanocyte reprogramming in vitiligo

Yang, F.; Yang, L.; Lai, S.; Yokota, M.; Kuroda, Y.; Yuki, T.; Takahashi, Y.; Sayo, T.; Namiki, T.; Goto, H.; Hiroyasu, S.; Sano, S.; Inoue, S.; Mizukami, Y.; Tsuruta, D.; Katayama, I.

doi:10.1101/2025.04.11.648350

bioRxiv · 10.1101/2025.04.11.648350

Altered laminin signaling destinates melanocyte reprogramming in vitiligo

Yang, F.·Yang, L.·Lai, S.·Yokota, M.·Kuroda, Y.·Yuki, T.·Takahashi, Y.·Sayo, T.·Namiki, T.·Goto, H.·Hiroyasu, S.·Sano, S.·Inoue, S.·Mizukami, Y.·Tsuruta, D.·Katayama, I.

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Abstract

Vitiligo is an acquired depigmenting skin disorder characterized by progressive melanocyte loss, but the cellular mechanisms driving this process remain unclear. Here, we identify melanocyte dedifferentiation as a central and reversible pathogenic mechanism in vitiligo. In healthy human skin, melanocytes reside within a basement membrane niche defined by dystroglycan-laminin-211 adhesion. In contrast, vitiligo lesions exhibit aberrant extracellular matrix remodeling, leading to an adhesion switch to integrin 3{beta}1-laminin-332 interactions. This shift promotes melanocyte dedifferentiation via Rho-F-actin-dependent activation of Hippo and MAPK pathways, resulting in c-Jun-mediated transcriptional changes. Dedifferentiated melanocytes lose their pigment-producing identity and acquire neural crest-like features with multilineage potential. Importantly, this process is reversible. Pharmacological inhibition of involved pathways restores melanocyte differentiation and induces repigmentation in both vitiligo mouse models and ex vivo patient skin. Notably, JAK inhibitors also promote redifferentiation independently of immune modulation. These findings uncover melanocyte dedifferentiation as a fundamental driver of vitiligo and a tractable therapeutic target, offering new opportunities for therapeutic intervention.

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Yang, F., Yang, L., Lai, S., Yokota, M., Kuroda, Y., Yuki, T., Takahashi, Y., Sayo, T., Namiki, T., Goto, H., Hiroyasu, S., Sano, S., Inoue, S., Mizukami, Y., Tsuruta, D., Katayama, I.. 2025-04-14. Altered laminin signaling destinates melanocyte reprogramming in vitiligo. https://doi.org/10.1101/2025.04.11.648350

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