Identifying the Molecular Characteristics of Migrating Melanocytes in Vitiligo Skin

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Abstract Vitiligo is a disease characterized by the accumulation of white patches on the skin, the direct result of immune-mediated melanocyte destruction. Narrow band NBUVB light therapy, the gold standard treatment for vitiligo, induces melanocytes to migrate from the hair follicle to re-pigment the epidermis. Surgical approaches can also replace the epidermal melanocyte reservoir depleted by the immune system, achieving similar re-pigmentation results as light therapy. While these therapies are partially successful, the observed re-pigmentation is rarely complete- areas of affected vitiligo skin often remain between re- pigmented areas. It is currently unclear whether this phenomenon is because the immune system removes melanocytes at the leading edge preventing a full response, vitiligo keratinocytes inhibit the migration of melanocytes, or melanocytes are not able to migrate completely to fill the gap migrate. We have recently developed non-invasive methods to visualize the migration of melanocytes laterally within the epidermis during vitiligo re-pigmentation, giving us the first glimpse of the dynamic epidermal melanocyte niche. In this application, we seek to use this novel technology to visualize the dynamics of vitiligo re-pigmentation and determine whether the extent of re-pigmentation is limited by local factors that limit melanocyte migration or by the immune system, which removes melanocytes. To gain a better sense of the cellular players that regulate the re-pigmentation process, we will perform single cell RNA sequencing on normal skin, skin that has partially responded to light therapy, and skin that did not respond to light therapy in order to: 1) define the molecular characteristics of migrating melanocytes; 2) identify whether there are unique populations of keratinocytes in vitiligo skin as compared to normal skin that could inhibit melanocyte migration; 3) identify putative immune signals and immune effectors that induce local destruction of melanocytes. Completion of these studies will be critical in developing new strategies to improve existing vitiligo therapies.