A macrophage-induced subpopulation of mesenchymal cells expressing Fcer1g contributes to wound-induced fibrosis

Abstract Fibrosis commonly occurs during adult skin wound healing, characterized by excessive extracellular matrix (ECM), leading to scarring. Mesenchymal cells, the primary ECM-producing population, are heterogeneous with varying fibrotic propensity during wound healing. While pro-fibrotic embryonically derived mesenchymal lineages have been identified, adult mesenchymal cells responsible for fibrosis are not yet fully characterized. In adult mice with conditional macrophage depletion during the early phase of wound healing, wounds exhibited attenuated fibrosis and a reduction in mesenchymal cell numbers. Single-cell RNA sequencing revealed a Fcer1g-expressing mesenchymal subpopulation that was significantly decreased following macrophage depletion. Targeted ablation of this cell population did not delay wound closure but resulted in diminished cutaneous scarring. During wound healing, these Fcer1g-expressing mesenchymal cells localized at the wound bed and exhibited a high proliferation rate. Fibronectin is secreted by macrophages and known to modulate fibrosis during wound healing. Wounds from EDA fibronectin-deficient mice contained significantly fewer Fcer1g-expressing mesenchymal cells. Our findings reveal a macrophage-induced adult mesenchymal subpopulation responsible for fibrosis.