Grant: Project Grant

More than 14 million severe skin wounds (burns, trauma, ulcers) are treated annually in North America. The annual cost of wound care in Canada is >$5 billion. Deficiencies in wound healing stem from an inability to regenerate functional dermis and a tendency of dermal fibroblasts to form scar. Scar tissue is dysfunctional and associated with chronic pain, immobility, and physical disfigurement, which are typically lifelong. Therapies that prevent scar, by promoting dermal regeneration, would have tremendous clinical value. We recently pioneered the use of captive reindeer to study adult mammalian skin regeneration (Sinha et al, Cell, 2022). Injury to back skin forms fibrotic scar, whereas identical wounds in antler skin (velvet) exhibit regeneration, complete with hair follicles and glands. This regenerative competence is associated with: 1) re-activation of embryonic genes in velvet fibroblasts, and 2) distinct communication between velvet fibroblasts and incoming immune cells. Our findings provide a 'blueprint' of cellular composition and signaling ensembles required to enable skin regeneration in adult mammals. Building on this, we will test the hypothesis that purposefully recapitulating velvet fibroblast function into otherwise scar-forming skin wounds, will reduce scar and promote regenerative healing. Aim 1 - To purposefully modulate dermal fibroblast function to enhance skin regeneration. Aim 2 -To characterize the cellular composition and signaling dynamics during acute human wound healing and how this compares to regenerative healing in reindeer. Aim 3 - To determine the mechanisms by which velvet dermal fibroblasts influence local immune cell function within the wound to enable regenerative healing. Impact: This project will provide new knowledge about the mechanisms underlying tissue fibrosis versus regenerative healing and inform development of future therapeutics designed to improve the quality of healing after severe skin injury/disease.