Plastic Surgery Research Council
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DYSREGULATION OF POST-TRANSLATIONAL COLLAGEN PATHWAYS MAY UNDERLIE HYPERTROPHIC AND KELOID PATHOPHYSIOLOGY: A ROLE FOR TARGETED IMMUNOSUPPRESSION THERAPY?
Presenter: Victor W Wong, MD
Co-Authors: You F; Januszyk M; Gurtner GC; Kuang AA
Stanford University

Hypertrophic scar (HTS) or keloid formation following cutaneous injury can produce severe dysfunction and disfiguration. The mechanisms that drive pathologic scarring are poorly understood and outcomes after multi-modality therapy remain suboptimal. The immunosuppressant drugs rapamycin (an inhibitor of mammalian target of rapamycin mTOR) and tacrolimus (a calcineurin inhibitor) have been shown to block inflammatory pathways and reduce transplant allograft fibrosis, suggesting that they may have a role in treating abnormal scar formation. Fibroblasts were harvested from human specimens (unwounded skin, HTS, and keloid scars) and treated with either rapamycin or tacrolimus for 72 hours. Genomewide transcriptional analysis was performed using Illumina BeadArray microarray systems. Principal components analysis was conducted using GeneSifter. Hierarchical clustering and pathways analysis were performed using MATLAB and Ingenuity Pathways Analysis, respectively. Taqman Gene Expression assays were used for quantitative PCR. Microarray analysis of HTS and keloid fibroblasts demonstrated modulation of programs related to cancer, proliferation, connective tissue development, and cell death. Pathways differentially regulated by HTS and keloid fibroblasts included hormone and arachidonic acid metabolism, eicosanoid signaling, and immune cytokines. Pathologic fibroblasts exhibited overexpression of collagen I and III that was significantly blocked with rapamycin but not tacrolimus. Post-translational collagen processing genes (PLOD, PCOLCE, P4HA) were significantly downregulated following rapamycin treatment in all fibroblast groups and found to be markedly overexpressed in HTS and keloid tissue. HTS and keloid fibroblasts exhibit distinct but overlapping transcriptional programs linked to excess matrix deposition. Targeting of mTOR but not calcineurin pathways in fibroblasts may have therapeutic potential for treating or preventing pathologic scarring. HTS and keloids demonstrate increased expression of post-translational collagen processing genes that may represent novel targets for anti-scar therapy.


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