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Wound healing in aged skin exhibits systems-level alterations in cellular composition and cell-cell communication

ABSTRACT: Delayed and often impaired wound healing in the elderly presents major medical, social, and economic challenges. A systematic understanding of the cellular and molecular changes that shape complex cell-cell communications in aged skin wounds is lacking. Here we use single-cell RNA sequencing to define baseline differences across epithelial/fibroblast/immune cell types in young and aged skin during homeostasis and identify major changes in their subset compositions, kinetics, and molecular profiles during wound healing. Our data uncover a more pronounced inflammatory phenotype in aged skin wounds, featuring more neutrophils, a previously unknown inflammatory/glycolytic Arg1Hi macrophage subset, and fewer dendritic cells, compared to young counterparts. Generalizing our computational tool CellChat to compare signaling changes in young vs. aged skin wounds, we find specific alterations in Arg1Hi macrophage-fibroblast signaling interactions and the overall cell-cell communication networks. Finally, our systems-level and experimental analyses uncover dysregulated growth factor, chemokine, and cytokine pathways (e.g., IL-1, Ccl19-Ccr7) in aged skin wounds. Our study exposes numerous cellular and molecular targets for future functional interrogation.

ORGANISM(S): Mus musculus

PROVIDER: GSE188432 | GEO | 2022/08/02

REPOSITORIES: GEO

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Project description:In adult mammals, skin wound healing has evolved to favor rapid repair through formation of fibrotic scar. Consequently, skin wounds are dysfunctional and lead to chronic disfigurement and disability, yet the biologic mechanisms that drive fibrosis and prevent tissue regeneration remain unknown. Here, we report that reindeer (Rangifer tarandus) antler velvet exhibits regenerative wound healing, whereas identical full-thickness injury in dorsal back skin forms fibrotic scar. This regenerative capacity is retained even following ectopic transplantation of velvet to a scar-forming site, demonstrating that this latent regenerative capacity is innate to velvet cells and independent of local factors derived from the growing antler. Single cell RNA-sequencing of uninjured skin revealed a marked divergence in resting fibroblast transcriptional states and immunomodulatory function. Uninjured velvet fibroblast shared a striking resemblance with human fetal fibroblasts whereas uninjured back skin fibroblasts exhibited an overrepresentation of pro-inflammatory genes resembling adult human fibroblasts. Identical skin injury resulted in site-specific fibroblast polarization; back fibroblasts exacerbated the inflammatory response, whereas velvet fibroblasts adopted an immunosuppressive state and reverted back to a regeneration-competent ground state. Consequently, velvet wounds exhibited reduced immune infiltrate, accelerated adoption of anti-inflammatory immune states and expedited resolution of immune response. This study demonstrates reindeer as a novel mammalian model to study adult skin regeneration (velvet) and scar formation (back skin) within the same animal. Our study underscores the importance of fibroblast heterogeneity in shaping local immune cell functions that ultimately polarize wound healing outcomes. Purposeful, acute modulation of fibroblast-mediated immune signaling represents an important therapeutic avenue to mitigate scar and improve wound healing.

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Wound healing in aged skin exhibits systems-level alterations in cellular composition and cell-cell communication

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