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Adipocytes Transition To Pro-fibrotic Fibroblasts And Contribute To Muscle Fibrosis Following Nerve Injury
Amanda F. Spielman, BS, Michelle Griffin, MD, PhD, Heather E. desJardins-Park, BS, Nicholas Guardino, BS, Kristian E. Bauer-Rowe, BS, Jason Guo, PhD, Jennifer Parker, BS, Darren Abbas, MD, Derrick Wan, MD, Michael T. Longaker, MD.
Stanford University, Stanford, CA, USA.

PURPOSE: Recent studies have suggested that interconversion between adipocytes and fibroblasts (the cellular mediators of skin scarring) occurs in the wound environment. Muscle fibrosis occurs following aging, muscle injury, and muscular dystrophies causing weakness and pain. The role of adipocytes in muscle fibrosis has not been fully explored. Our study examines whether mature adipocytes participate in muscle fibrosis following nerve injury via conversion into dermal fibroblasts.METHODS: AdipoqCre transgenic driver mice were crossed to R26mTmG reporter mice to generate AdipoqCre;ROSA26mTmG mice, in which mature adipocytes (Adipoq/adiponectin-expressing cells) express green fluorescent protein (GFP), and all other cells express a red fluorescent protein (RFP). AdipoqCre;ROSA26mTmG mice underwent sciatic nerve injury per established protocol (Fig.1A). Injured tibialis anterior and gluteus maximus muscle was harvested at postoperative day-14 (POD14) and underwent immunofluorescent staining for fibroblast (collagen type IV/col-IV, alpha-smooth muscle actin/a-SMA) and adipocyte (perilipin) cell markers. To achieve local adipocyte ablation, AdipoqCre;ROSA26mTmG;R26tm1(HBEGF)Awai mice were generated and wounded, and diphtheria toxin (DT;400ng/mouse) was injected into the muscle at the nerve injury site. DT- and vehicle control-treated muscle underwent histologic analysis (Fig.1B).RESULTS: We identified a significantly greater number of adiponectin-lineage-positive cells (GFP+) within injured muscle at POD14 compared to uninjured muscle (*p<0.05,n=5). The GFP+ cells that infiltrated the muscle injury exhibited upregulation of fibrotic markers including col-IV and α-SMA, and downregulation of adipocyte markers including perilipin, indicating conversion of adipocytes into pro-fibrotic fibroblasts. DT-induced ablation of Adipoq-lineage-positive cells resulted in reduced muscle scarring, with decreased collagen deposition compared to vehicle-control injured muscle (*p<0.05,n=5).CONCLUSION: Our study demonstrates that adipocytes undergo conversion to pro-fibrotic fibroblasts in response to nerve injury and contribute to muscle fibrosis. Targeted adipocyte ablation resulted in reduced muscle scarring, suggesting that adipocyte-derived fibroblasts are important contributors to muscle fibrosis.


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