Universität zu Köln

Rosendahl, Ann-Helen S ORCID: 0000-0001-7968-0990, Bornikoel, Anna ORCID: 0000-0002-1921-7205, Zeinert, Isabel ORCID: 0000-0001-5790-7306, Keufgens, Lena ORCID: 0000-0001-6892-7302, Tellkamp, Frederik ORCID: 0000-0002-0473-7320, Kleinenkuhnen, Niklas, Baar, Till ORCID: 0000-0002-6744-1463, Schönborn, Katrin, Krüger, Marcus ORCID: 0000-0002-5846-6941, Tresch, Achim ORCID: 0000-0002-4146-6371, Brachvogel, Bent ORCID: 0000-0002-3923-0554, Eckes, Beate ORCID: 0000-0002-0936-0702, Moinzadeh, Pia ORCID: 0000-0002-8784-8615 and Krieg, Thomas ORCID: 0000-0001-5616-8476 (2026). Identification of novel fibroblast subsets in diffuse cutaneous systemic sclerosis. Annals of the Rheumatic Diseases, 85 (4). pp. 680-692. Elsevier. ISSN 0003-4967

PDF 1-s2.0-S0003496725045947-main.pdf Bereitstellung unter der CC-Lizenz: Creative Commons Attribution. Download (4MB)

Abstract

Objectives: Systemic sclerosis (SSc) is an autoimmune-driven fibrotic disease, characterised by excessive extracellular matrix (ECM) deposition and fibroblast activation. Our study aimed to identify novel fibroblast subpopulations in SSc and determine their functional role. Methods: We performed single-cell RNA sequencing on cultured dermal fibroblasts from healthy donors and patients with diffuse cutaneous SSc, verified selected, specific genes at the protein level and used siRNA knockdown experiments to provide evidence for a functional role of these proteins. Results: SSc fibroblasts revealed high heterogeneity and in specific activated subsets strong upre- gulation of CD9 and four and a half LIM domain 1 (FHL1), previously described as a muscle- related protein. Overexpression of FHL1 and CD9 was also detected in fibroblast subsets in patient skin. CD9 was associated with the regulation of FHL1 expression. Downmodulation of FHL1 in primary skin fibroblasts correlated with downregulation of the vestigial-like family member 3 (VGLL3) gene, which is known to be expressed in myofibroblasts in a stiff and fibrotic environment and to upregulate collagen synthesis. Further, VGLL3 was confirmed to be upregu- lated in SSc donor skin. Conclusions: Our study identified novel fibroblast subsets in SSc, characterised by CD9 and/or FHL1 upregulation. The data indicate a functional role of FHL1 in fibroblasts and its involve- ment in the regulation of ECM production and provide a new mechanistic link to VGLL3 regula- tion. Our findings suggest new avenues for therapeutic exploration targeting the perpetuating fibroblast activation by the fibrotic environment.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Rosendahl, Ann-Helen S UNSPECIFIED https://orcid.org/0000-0001-7968-0990 UNSPECIFIED Bornikoel, Anna UNSPECIFIED https://orcid.org/0000-0002-1921-7205 UNSPECIFIED Zeinert, Isabel UNSPECIFIED https://orcid.org/0000-0001-5790-7306 UNSPECIFIED Keufgens, Lena UNSPECIFIED https://orcid.org/0000-0001-6892-7302 UNSPECIFIED Tellkamp, Frederik UNSPECIFIED https://orcid.org/0000-0002-0473-7320 UNSPECIFIED Kleinenkuhnen, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Baar, Till UNSPECIFIED https://orcid.org/0000-0002-6744-1463 UNSPECIFIED Schönborn, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Krüger, Marcus UNSPECIFIED https://orcid.org/0000-0002-5846-6941 UNSPECIFIED Tresch, Achim UNSPECIFIED https://orcid.org/0000-0002-4146-6371 UNSPECIFIED Brachvogel, Bent UNSPECIFIED https://orcid.org/0000-0002-3923-0554 UNSPECIFIED Eckes, Beate UNSPECIFIED https://orcid.org/0000-0002-0936-0702 UNSPECIFIED Moinzadeh, Pia UNSPECIFIED https://orcid.org/0000-0002-8784-8615 UNSPECIFIED Krieg, Thomas UNSPECIFIED https://orcid.org/0000-0001-5616-8476 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-812797
Identification Number:	10.1016/j.ard.2025.11.027
Journal or Publication Title:	Annals of the Rheumatic Diseases
Volume:	85
Number:	4
Page Range:	pp. 680-692
Number of Pages:	13
Date:	April 2026
Publisher:	Elsevier
ISSN:	0003-4967
Language:	English
Faculty:	Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Dermatologie > Klinik und Poliklinik für Dermatologie und Venerologie Faculty of Medicine > Kinder- und Jugendmedizin > Klinik und Poliklinik für Kinder- und Jugendmedizin Faculty of Medicine > Medizinische Statistik und Bioinformatik > Institut für Medizinische Statistik und Bioinformatik � IMSB Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81279