Development of a multi-organ single-cell atlas of systemic sclerosis reveals shared and tissue-specific pathogenic pathways.
- 1Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
Abstract
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.
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BibTeX
@misc{iperi2026development,
title = {{Development of a multi-organ single-cell atlas of systemic sclerosis reveals shared and tissue-specific pathogenic pathways.}},
author = {C. Iperi and C. Geiss and M. Lugar and P. Stauffer and N. Vlachogiannis and A. Hofman and A. Khmelevskaya and P. P. Sfikakis and A.-M. Hoffmann-Vold and R. Micheroli and C. Seiler and O. Distler and C. Ospelt and M. Elhai},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761913},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761913v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Development of a multi-organ single-cell atlas of systemic sclerosis reveals shared and tissue-specific pathogenic pathways.
AU - C. Iperi
AU - C. Geiss
AU - M. Lugar
AU - P. Stauffer
AU - N. Vlachogiannis
AU - A. Hofman
AU - A. Khmelevskaya
AU - P. P. Sfikakis
AU - A.-M. Hoffmann-Vold
AU - R. Micheroli
AU - C. Seiler
AU - O. Distler
AU - C. Ospelt
AU - M. Elhai
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761913
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761913v1
AB - 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.
ER -