69. Cross-Species Conservation of Cellular Phenotypes in the Wound Microenvironment

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PURPOSE: Tissue repair is a complex but critical process. The skin represents the most readily accessible organ system in which to study repair. Wound healing consists of three canonical phases: inflammation, proliferation, and remodeling, and is well conserved throughout evolution. Pathologic wound repair can be characterized as either over-healing (e.g., hypertrophic scars, keloids) or under-healing (chronic). Fibroblasts are the cell type most typically believed to drive both processes. Prior work has attempted to characterize fibroblasts at single cell resolution, however these studies have been limited to single species and therefore cannot assess the conservation of these critical processes within the wound microenvironment and their impact on successful healing. METHODS: To assess conservation of cellular phenotypes, we systematically analyzed all scRNA-seq wound studies in the public domain, evaluating all datasets published from January 2014 until December 2023. Separate queries were applied for human, house mouse, pig, reindeer, spiny mouse, lamb, axolotl, and zebrafish datasets in GEO and ArrayExpress, as well as independent Pubmed queries. We screened 5,884 datasets and publications across all organisms. This identified 12 human, 32 mouse, 1 pig, and 1 reindeer datasets, as well as 3 datasets from the Acomys spiny mouse and 1 from axolotl, comprising more than 1.5 million cells spanning 324 individual scRNA-seq samples. We analyzed datasets on a per-species basis employing sketch-based sampling of the data in conjunction with disk/memory read optimization. We applied three independent approaches for data integration: Harmony, scVI, and FastMNN. RESULTS: We identified strong conservation of cell subpopulations across all six species. Fibroblasts in particular were consistently found to occupy 4 broad transcriptional programs, which we define as antigen-presenting wound associated fibroblasts (apWAFs), inflammatory and immunomodulatory fibroblasts (iWAFs), mechanically-responsive and myofibroblastic fibroblasts (mWAFs), and steady state fibroblasts (ssWAFs). Interestingly, the mWAF population expanded considerably in all active wounds compared to normal tissue in each species, and the ssWAF population receded. Interestingly, the apWAF population was also considerably elevated in all wounds. We additionally identified an endothelial cell population (“tip” cells) and a pericyte population (“CD248+”) that mirrored the mWAF patterning in wounds. Scar tissue (healed wounds) had transcriptional profiles that were intermediate between unwounded tissue and active wounds, suggesting that healed wounds never reach their unwounded state. We also observed considerable elevation of mWAFs in keloids compared to normal scars, and that mWAFs were elevated in areas of the body associated with the most pressure, suggesting that these cells are in fact mechanically-responsive. CONCLUSION: Collectively, this research strongly suggests that certain key cell subpopulations are conserved across multiple species, but in their cellular proportions and also in their inferred function. By targeting populations consistently associated with poor wound healing outcomes, it may be possible to develop novel therapeutics.

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