Dormant melanocytes may offer new treatment path in vitiligo

Under normal conditions (left), melanocytes adhere to laminin-211 in the basement membrane through dystroglycan, maintaining their mature pigment-producing state. In vitiligo (right), remodeling of the basement membrane increases laminin-332 and promotes integrin α3β1-mediated adhesion, activating signalling pathways, including c-Jun, that drive melanocyte dedifferentiation and loss of pigment production. Image courtesy Osaka Metropolitan University

Researchers report that pigment-producing cells may persist in vitiligo lesions in a reversible, dedifferentiated state, challenging the view these cells are permanently destroyed.

Melanocytes in vitiligo lesions may enter a dormant, less specialized state that could be pharmacologically reversed, according to a study published in Nature Communications.

The findings suggest that future therapies may be able to restore pigmentation by reactivating melanocytes already present in affected skin, rather than focusing solely on suppressing the autoimmune response associated with the disease.

Vitiligo is an acquired depigmenting disorder in which immune-mediated injury leads to the progressive loss of functional melanocytes. Yet the conventional model has not fully explained why some lesions repigment or why treatment can restore colour in areas thought to lack melanocytes.

Researchers at Osaka Metropolitan University identified what they described as a “dedifferentiation-like” shift in melanocytes. In this state, the cells lose mature pigment-producing functions and acquire features associated with more primitive, neural crest-like cells.

“This study uncovers a new mechanism underlying the development of vitiligo, which could change how we treat the disease,” Dr. Lingli Yang, a study investigator, said in a press release.

The process appears to be driven partly by remodelling of the basement membrane. In healthy skin, melanocytes interact with laminin-211 through dystroglycan. In vitiligo, reduced laminin-211 and increased laminin-332 were associated with a shift toward adhesion mediated by integrin α3β1.

That change correlated with Rho–F-actin remodelling and alterations in Hippo, MAPK and c-Jun signalling, along with reduced expression of pigmentation-related genes. The investigators proposed a self-reinforcing cycle in which basement-membrane changes promote melanocyte dedifferentiation, while the altered cells become less capable of maintaining a healthy extracellular environment.

Pharmacological modulation partially reversed these changes in mouse models and ex vivo human skin, restoring markers of melanocyte differentiation and pigment-related gene expression. JAK inhibition also promoted redifferentiation.

“This was an exciting aspect of our research, as it suggests that changing gene expression isn’t permanent and this process may be reversible,” Dr. Yang said. “We found that drugs were able to restore melanocyte function and pigmentation-related characteristics. The next step will be to perform clinical studies to see if this approach is a viable way to manage the disease.”

The results remain preclinical, and whether targeting melanocyte adhesion or redifferentiation can safely produce durable repigmentation in patients will require clinical investigation.