Development of a multi-organ single-cell atlas of systemic sclerosis reveals shared and tissue-specific pathogenic pathways

Objectives

Systemic sclerosis (SSc) is a multi-organ autoimmune disease for which no broadly effective disease-modifying treatment exists. We developed an integrated multi-organ single-cell atlas of SSc to identify shared and organ specific disease-associated transcriptional programmes and potential therapeutic targets.

Methods

We integrated single-cell RNA-sequencing data from skin, lung, synovium, and peripheral blood mononuclear cells (six studies, 401,902 cells, 90 individuals) using Harmony. Pseudobulk differential expression and gene set enrichment analysis were performed at the tissue cell-compartment, cell-type, and subpopulation levels, including independent reclustering of lymphoid, myeloid and fibroblast populations.

Results

Disease-associated transcriptional programmes showed marked tissue dependence, even within the same cell lineage, highlighting the importance of organ-specific mechanisms in SSc. Nevertheless, recurrent extracellular matrix (ECM) remodelling programmes were identified in lung, skin and synovium, and interferon signalling programmes in skin, synovium and peripheral blood mononuclear cells, across immune and fibroblast cell populations. Although no subpopulation was exclusive to SSc, a shared myofibroblast subpopulation expressing SFRP2, COL1A1, POSTN, ACTA2 , and COMP was identified across lung, skin, and synovium. In addition, perivascular and mitotic fibroblast subpopulations exhibited both profibrotic and inflammatory signatures, including interferon- and IL-2-related signalling programmes.

Conclusions

SSc is characterised by two complementary axes: a tissue-dependent cellular programme and a recurrent fibrotic and interferon-associated signature extending across multiple organs and cell populations. These findings are consistent with current organ-based therapeutic approaches while highlighting interferon signalling as a potential multi-organ therapeutic target. The resulting interactive single-cell atlas provides a resource for investigating shared and organ-specific disease mechanisms and guiding future therapeutic research.

Abstract Figure

Top: study overview: 90 individuals, 6 studies and 401,902 cells across four organs: lung (7 SSc, 10 CTRL), skin (27 SSc, 10 CTRL), PBMCs (21 SSc, 6 CTRL) and synovium (6 SSc, 3 CTRL). In addition, the levels of resolution analysed (organs, cell compartments, cell types and cell subpopulations), with the number of units included at each level. Centre right: summary table of shared and organ-specific activated pathways in SSc versus CTRL across organs (plus and minus signs indicate increased and decreased activity in SSc, respectively). Centre left: pathogenic fibroblast subpopulations shared across organs (myofibroblast, perivascular and mitotic), with their activated pathways. Bottom: zoom on the cell types contributing to the shared and organ-specific programmes in each organ. SSc = systemic sclerosis; CTRL = controls; PBMCs = peripheral blood mononuclear cells; ECM = extracellular matrix/collagen metabolism; IFN = interferon signalling (IFNα-β, type I; IFNγ, type II); TNF = tumour necrosis factor signalling; IL = interleukin; ATP = ATP synthesis.

Key messages