Adipocytes the Forgotten Culprit in Skin Fibrosis: Exploring the Mechanism of Fat Driven Skin Fibrosis

Abstract

INTRODUCTION: Adipocytes have previously been implicated in skin wound healing in both metabolic and nonmetabolic roles. We hypothesized that mature adipocytes directly participate in wound repair via conversion into fibroblasts and that adipocyte-derived fibroblasts contribute to skin scarring. METHODS: AdipoqCre transgenic driver mice were crossed to R26mTmG reporter mice to generate AdipoqCreERT;ROSA26mTmG mice to perform lineage tracing of mature adipocytes. To achieve local adipocyte ablation AdipoqCre;ROSA26mTmG;R26tm1 (HBEGF) Awai mice were generated and wounded, and diphtheria toxin (DT) was injected into the wound base. DT- and vehicle control-treated wounds underwent histologic analysis. Last, we performed scRNAseq on wounded and unwounded tissue to identify fibrotic fibroblast subpopulations. RESULTS: Using our AdipoqCre;ROSA26mTmG adipocyte lineage-tracing model (Fig. A), we identified significantly greater number of adiponectin lineage-positive cells (GFP+) within wounds at postoperative day 14 (POD-14) compared with unwounded skin (*p < 0.05, n = 6; Fig. B). FACS further confirmed that the GFP+ cells were fibroblasts and increased to 10% at POD-14 (Fig. C). Compared with typical subcutaneous adipocytes, the GFP+ cells exhibited upregulation of fibroblast markers and downregulation of adipocyte markers (Fig. D). DT-induced ablation of Adipoq lineage-positive cells (Fig. E) exhibited reduced scar thickness (Fig. F) and collagen deposition at POD-14 compared with control wounds (*p < 0.05, n = 6; Fig. G). scRNAseq analysis revealed novel markers for distinct mechanosensitive fibroblast subpopulations responsible for scar formation (Fig. H).FigureCONCLUSION: Our findings strongly suggest that mature adipocytes in the skin undergo conversion to profibrotic fibroblasts in response to injury. Local adipocyte ablation resulted in reduced scarring, suggesting that adipocyte-derived fibroblasts are important contributors to wound fibrosis. These findings together suggest that adipocyte mechanosensitive fibroblast subpopulations drive dermal scar formation.