Single-cell RNA-seq reveals conserved and divergent cellular states across wound types and species

Abstract

Chronic wounds, such as diabetic foot ulcers, fail to progress through the normal healing process and impose a significant burden on healthcare systems. While previous single-cell studies have characterized specific wound conditions, a unified understanding of the shared and distinct cellular landscapes across diverse wound microenvironments has been lacking. Therefore, we integrated over 500,541 cells from patients and mice across multiple wound conditions, including acute wound, diabetic foot ulcer, and venous ulcer as well as their healing outcome. Fibroblast-focused analysis identified a bifurcation in differentiation trajectories and identified STAT3 as a potential regulator of a reparative program in chronic wound. Furthermore, we discovered immune dysfunctions in non-healed chronic wounds, contrasting the quiescent memory-like T cells and TIMP1+ macrophages in healed chronic wounds with the exhausted T cells and foamy SPP1+ macrophage enriched in non-healed chronic wounds. Finally, we translated these results into a clinically applicable three-gene signature (CHI3L1, TIMP1, and SPP1) that accurately predicts chronic wound healing. To support wound biology community, we developed WoundSCAtlas, an interactive web resource for exploring diverse wound pathologies. In conclusion, this work provides a comprehensive and cross-species landscape of chronic wound healing, identifying conversed wound outcome-associated molecular programs, predictive biomarker, and interactive data resource.