Association between stem cell growth factor beta and fibrotic skin diseases

Immune dysregulation is implicated in fibrotic skin pathogenesis. However, causal inflammatory cytokines remain inadequately characterized. To identify inflammatory cytokines with potential causal roles in fibrotic skin disorders using integrative genetic and experimental approaches. Two-sample Mendelian randomization (MR) analysis was conducted utilizing summary statistics from genome-wide association studies (GWAS) for 41 inflammatory cytokines and four fibrotic skin diseases. Differences in selected inflammatory cytokine levels in tissues, sera and cells between hypertrophic scar (HS) patients and healthy volunteers were investigated. In addition, primary human HS fibroblasts were stimulated using recombinant proteins of selected inflammatory cytokines. The effects of recombinant proteins on proliferation, apoptosis, migration and collagen deposition of fibroblasts were examined by EdU (5-ethynyl-2'-deoxyuridine), annexin V-FITC/PI double staining, Transwell migration and western blot assay, respectively. The levels of stem cell growth factor beta (SCGF-β) were significantly associated with all four fibrotic skin diseases, with OR=1.24 (p=0.016) for HS, OR=0.77 (p=0.048) for keloid, OR=1.20 (p=0.022) for lichen sclerosus, and OR=1.40 (p=0.021) for systemic sclerosis. Moreover, SCGF-β levels in HS tissues and sera were elevated. Fibroblasts cultured with recombinant proteins of SCGF-β showed enhanced proliferation and collagen production, reduced apoptosis (p<0.05), and no significant effect on migration (p>0.05). This study establishes SCGF-β as a putative causal mediator of fibrotic skin diseases, with experimental validation for HS, demonstrating its pro-fibrotic activity.