1529 Impact of serotonin signaling on skin homeostasis and wound healing

Improving delayed healing remains extremely challenging in the absence of new drugs approved. A potential role of serotonin signaling on skin homeostasis has recently been uncovered. In addition, serotonin promotes tissue regeneration through stem cells activation in a 5HT1B receptor-dependent mechanism in other organs than skin. Using publicly available datasets of single cell RNA sequencing of mouse skin, we found that 5HTR2A receptor and serotonin transporter SLC6A4 have an ubiquitous expression in resident skin cells, and that 5HTR1A and 5HTR1D receptors are mainly expressed in the dermis. 5-HT receptors expression also varied during skin wounding. To dissect the role of serotonin signaling on skin homeostasis and wound healing, we used mice knocked-out for Tryptophan Hydroxylase 1 (Tph1), the rate-limiting enzyme in serotonin synthesis pathway. Tph1-/- mice lacking serotonin in peripheral organs displayed altered wound healing compared with controls. In addition, we used several modulators of serotonin signaling to study their topical and systemic effect on skin wound healing in wild type mice and in mice with altered wound healing. We showed that drug X, a partial agonist of specific 5-HT receptors, significantly decreased wound area by enhancing neoepidermis formation and epidermal keratinocytes proliferation, as well as stimulating angiogenesis in wild type mice. Drug X also enhanced wound closure in a mice model displaying clobetasol-induced skin atrophy. In conclusion, we aim to provide a better understanding of serotonin signaling in mouse skin homeostasis and repair, in order to develop new therapeutic strategies to treat altered wound healing.