Clark, Kristina EN;
Xu, Shiwen;
Attar, Moustafa;
Ong, Voon H;
Buckley, Christopher D;
Denton, Christopher P;
(2025)
Characterisation of a pathogenic non-migratory fibroblast population in systemic sclerosis skin.
JCI Insight
, Article e185618. 10.1172/jci.insight.185618.
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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 non-migratory "resident" population of fibroblasts from skin biopsies after outgrowth of explant "migratory" cells. These non-motile resident fibroblasts were compared with migratory cells from the same biopsy, using functional studies, bulk and scRNAseq, and localised in situ by multichannel immunofluorescence. Migratory and resident fibroblast populations in SSc showed distinct pro-fibrotic characteristics and gene expression for pathogenic pathways differing by stage and autoantibody subgroup. TGFβ signalling was highly active in migratory fibroblasts in early stage dcSSc. Conversely, resident fibroblasts had less upregulated TGFβ signalling, especially in late dcSSc. Increased chemokine expression was a hallmark of resident fibroblasts at all stages. In vitro studies confirmed differential response to TGFβ1 and CCL2 between migratory and resident cells. We suggest that migratory fibroblasts are especially important in early skin disease whereas non-migratory 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.
| Type: | Article |
|---|---|
| Title: | Characterisation of a pathogenic non-migratory fibroblast population in systemic sclerosis skin |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/jci.insight.185618 |
| Publisher version: | https://doi.org/10.1172/jci.insight.185618 |
| Language: | English |
| Additional information: | Copyright © 2025, Clark et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Autoimmune diseases, Autoimmunity, Fibrosis, Immunology, Inflammation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10207514 |
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