Single cell RNA seq reveals the pro-regenerative phenotype of thrombospondin-2 deficient dermal fibroblasts.

Fibroblasts display complex functions linked to distinct gene expression profiles. These profiles influence matrix production, cell communication, and tissue development and repair. Thrombospondin-2 (TSP2), produced by fibroblasts, is a potent angiogenesis inhibitor and negatively associated with tissue repair. Single-cell RNA sequencing (scRNA-seq) on WT and TSP2 KO skin fibroblasts demonstrate distinct cell heterogeneity. Specifically, we found an enrichment of Sox10 + multipotent progenitor cells, identified as Schwann precursor cells, in TSP2 KO fibroblasts, while fibrosis-related subpopulations decreased. Immunostaining of mouse back skin wounds and cells validated the increase of this Sox10 + population. Furthermore, in silico analysis suggested enhanced PDGF-β-mediated pro-survival and inhibited BMP4-mediated differentiation signaling pathways. These molecular and functional alterations likely contribute to improved healing and increased neurogenesis in TSP2 KO wounds. Overall, our findings describe the heterogeneity of dermal fibroblasts (DFs) and identify pro-regenerative features of TSP2 KO fibroblasts.