Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
Department of Biomedical Engineering, Yale University, New Haven, CT, USA; Vascular Biology and Therapeutics, Yale University, New Haven, CT, USA.
Morgridge Institute for Research, Madison, WI, USA.
Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
McCaig Institute, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Biology, University of Kentucky, Lexington, KY, USA.
Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; McCaig Institute, University of Calgary, Calgary, AB, Canada; Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada; McCaig Institute, University of Calgary, Calgary, AB, Canada.
Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada; Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada; Hotchkiss Brain Institute, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Calgary, AB, Canada. Electronic address: jeff.biernaskie@ucalgary.ca.
Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler skin (velvet) regenerate, whereas back skin forms fibrotic scar. Single-cell multi-omics reveal that uninjured velvet fibroblasts resemble human fetal fibroblasts, whereas back skin fibroblasts express inflammatory mediators mimicking pro-fibrotic adult human and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: back skin fibroblasts amplify myeloid infiltration and maturation during repair, whereas velvet fibroblasts adopt an immunosuppressive phenotype that restricts leukocyte recruitment and hastens immune resolution. Ectopic transplantation of velvet to scar-forming back skin is initially regenerative, but progressively transitions to a fibrotic phenotype akin to the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration is diminished by intensifying, or enhanced by neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent a powerful comparative model for interrogating divergent wound healing outcomes, and our results nominate decoupling of fibroblast-immune interactions as a promising approach to mitigate scar.
