While past studies have suggested that plasticity exists between dermal fibroblasts and adipocytes, it remains unknown whether fat actively contributes to fibrosis in scarring. We show that adipocytes convert to scar-forming fibroblasts in response to Piezo-mediated mechanosensing to drive wound fibrosis. We establish that mechanics alone are sufficient to drive adipocyte-to-fibroblast conversion. By leveraging clonal-lineage-tracing in combination with scRNA-seq, Visium, and CODEX, we define a mechanically naive fibroblast-subpopulation that represents a transcriptionally intermediate state between adipocytes and scar-fibroblasts. Finally, we show that Piezo1 or Piezo2-inhibition yields regenerative healing by preventing adipocytes activation to fibroblasts, in both mouse-wounds and a novel human-xenograft-wound model. Importantly, Piezo1-inhibition induced wound regeneration even in pre-existing established scars, a finding that suggests a role for adipocyte-to-fibroblast transition in wound remodeling, the least-understood phase of wound healing. Adipocyte-to-fibroblast transition may thus represent a therapeutic target for minimizing fibrosis via Piezo-inhibition in organs where fat contributes to fibrosis.
In adult mammals, skin wounds typically heal by scarring rather than through regeneration. In contrast, "super-healer" MRL mice have the unusual ability to regenerate ear punch wounds, yet the molecular basis for this regeneration remains elusive. Here, in hybrid crosses between MRL and non-regenerating mice, we use allele-specific gene expression to identify cis-regulatory variation associated with ear regeneration. Analyzing three major wound cell populations, we identified extensive strain- and tissue- specific cis-regulatory divergence associated with differences in healing outcomes. Genes with cis-regulatory differences specifically in fibroblasts were associated with wound healing phenotypes and pathways, and were enriched near genetic markers associated with ear-healing in a genetic cross. Finally, we demonstrated that one of these genes, Cfh, could be applied ectopically to accelerate wound repair and induce regeneration in typically fibrotic wounds. Overall, our results provide insight into the molecular drivers of regeneration in MRL mice with potential clinical implications.
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