Characterization of a pathogenic nonmigratory fibroblast population in systemic sclerosis skin
Year: 2025
Type: article
Abstract: Fibroblasts are central to pathogenesis of systemic sclerosis (SSc). However, studies of conventional explant fibroblast cultures incompletely reflect disease biology and treatment response. We isolated a second nonmigratory "resident" population of fibroblasts from skin biopsies after outgrowth of explant "migratory" cells. These nonmotile resident fibroblasts were compared with migratory cells from the same biopsy, using functional studies, bulk and single-cell RNA-seq, and localized in situ by multichannel immunofluorescence. Migratory and resident fibroblast populations in SSc showed distinct profibrotic characteristics and gene expression for pathogenic pathways differing by stage and autoantibody subgroup. TGF-β signaling was highly active in migratory fibroblasts in early-stage diffuse cutaneous SSc (dcSSc). Conversely, resident fibroblasts had less upregulated TGF-β signaling, especially in late-stage dcSSc. Increased chemokine expression was a hallmark of resident fibroblasts at all stages. In vitro studies confirmed differential response to TGF-β1 and CCL2 between migratory and resident cells. We suggest that migratory fibroblasts are especially important in early skin disease, whereas nonmigratory fibroblasts may have a regulatory role and contribute more to fibrosis in later-stage disease. Thus, we have identified a pathogenic fibroblast population in SSc, not isolated by conventional explant culture, that could play an important role in fibrosis and be targeted therapeutically.
Source: JCI Insight
Authors: Kristina E.N. Clark, Shiwen Xu, Moustafa Attar, Voon H. Ong, Christopher D. Buckley, Christopher P. Denton
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Medical Research Council, UCB Pharma
OpenAlex ID: W4409448078