Neuroimmune Control of Scarless Skin Regeneration

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Project Abstract Vertebrates repair skin injury through two fundamental biological processes: scar formation and tissue regeneration. Human skin generally heals with scar formation, which may cause severe emotional distress and physical disability. One hundred million new scars appear annually in the US, and although many products are marketed for scar prevention, their results are modest. Consequently, the elucidation of mechanisms underlying scar formation and tissue regeneration may result in new insights with far reaching implications in the development of therapeutics that promotes skin regeneration after wounding. Ear hole closure and wound- induced hair neogenesis (WIHN) are two instances where adult mammals can regenerate full-thickness skin wounds without scar formation, including hair follicles and sebaceous glands. Using both models, we demonstrated that topical pharmacologic activation of transient receptor protein A1 (TRPA1), a receptor expressed on skin sensory nerves promotes regeneration. This improved healing depends on dermal dendritic cells activating γδ Τ cells through interleukin 23. Strikingly, local activation of TRPA1 promotes tissue regeneration in distant injured areas, suggesting that a circulating factor may be induced with an accompanying paracrine mechanism. Our results reveal a new cutaneous neuroimmune-regeneration pathway, and a fundamental advance for the field would be a more comprehensive molecular understanding of signaling pathways involving multiple cell types that promotes mammalian tissue regeneration. In Aim 1, we use a combination of optogenetics, mouse models, and single-cell genomics to investigate whether TRPA1 on skin sensory nerves is necessary and sufficient to promote tissue regeneration in our two wounding models and to identify the molecular mechanisms of how TRPA1 expressing neurons locally activate immune cells. In Aim 2, we use mouse models to elucidate how γδ T cells and their effector cytokines promote systemic scarless tissue regeneration in our two wounding models. Together, our aims define mechanisms of cellular cross talk between nerves, immune cells, and skin, and successful completion will contribute to our overall goal of developing novel therapies to promote scarless skin regeneration in humans.