Summary:
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.
Overall Design:
Droplet-based single cell RNA-seq experiments were performed to identify molecular differences between young (7-week-old) and aged (88-week-old) skin from unwounded, 4-, and 7-day post-wounding skin.
