Grant: Project Grant

More than 14M severe skin wounds (burns, trauma, ulcers) are treated annually in North America. Because there are no effective treatments, the functional impairments (chronic pain/itch, immobility, disfigurement) are lifelong. The annual cost of wound care in Canada is >$4B. The inability to regrow healthy skin after injury is due to the tendency of dermal fibroblasts to form scar tissue. Strategies that prevent fibroblasts from forming scar are desperately needed to restore quality of life after skin injury and reduce the associated health care burden. Our recent work showed that after severe skin injury, wound healing fibroblasts are not predestined to form scar, but in some contexts can activate gene-expression programs that support skin regeneration (including hair follicles, glands). Importantly, regenerative wounds harbored distinct compositions of immune cells suggesting that altering the wound immune environment could enable regeneration. Indeed, we found that preventing recruitment of mature neutrophils improved regeneration, while removing innnervation promoted scar. We hypothesize that immune cell and sensory signaling are critical regulators of fibroblast function, regenerative competence and ultimately determine the quality of wound healing. Aim 1. To determine the cellular mechanisms responsible for improving regeneration after Ly6G/C treatment. Aim 2. To characterize the role of peripheral sensory inputs in regulating immune cell and fibroblast dynamics during regeneration. Aim 3. To identify signalling pathways that regulate myeloid maturation and modulate these pathways to enhance skin regeneration. This project will provide new insight into the interplay between immune cells, sensory innervation and dermal fibroblasts during wound healing and how purposefully modulating this cellular dialogue can promote skin regeneration. This knowledge will inform development of new treatments to improve outcomes after severe skin injury or disease.