Matrix stiffness regulates profibrotic fibroblast differentiation and fibrotic niche activation in systemic sclerosis

Ueberall L, Mohammadian H, Demmler R, Ariza Y, Tripal P, Anchang CG, Weber S, Angeli MR, Raimondo MG, Chang J, Huang K, Distler JH, Distler O, Rauber S, Schett G, Ramming A, Ramming A (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

DOI: 10.1016/j.ard.2025.05.016

Abstract

Objectives: Fibrosis progression in systemic sclerosis (SSc) has been attributed to matrix stiffness. Despite extensive research on fibroblast heterogeneity and subset imbalances in fibrotic disorders, the interplay between biomechanical cues and fibroblast dynamics remains largely unexplored. Here, we investigate how matrix stiffness alters fibroblast transcriptional state and influences lineage specification in fibrotic skin. Methods: We employed a collagen I-based 3-dimensional culture system to expose fibroblasts to varying levels of matrix stiffness, followed by RNA sequencing to identify stiffness-responsive gene expression signature. We integrated single-cell RNA sequencing data from SSc and healthy skin samples to identify fibroblast subsets associated with this signature. Spatial transcriptomic analyses were performed to localise these fibroblasts and their associations with the fibrotic niche. Results: Fibroblasts subjected to increased matrix stiffness exhibited a distinct transcriptional signature, amplified in SSc patients and enriched in PI16⁺ progenitor-like cells within the SFRP2⁺ fibrotic compartment. Further analysis indicated that PI16⁺ fibroblasts are predisposed to SFRP2⁺ COMP⁺ PU.1⁺ myofibroblasts differentiation, whereas blocking mechanotransduction by focal adhesion kinase inhibition disrupts this process, suggesting that matrix stiffness is a key driver of this lineage transition. Spatial mapping revealed colocalisation of the PI16⁺ and COMP⁺ subsets in extracellular matrix-dense regions, highlighting the functional relevance of this relationship in fibrotic progression. Conclusions: Our findings suggest that increased matrix stiffness promotes fibroblast precursor differentiation into SFRP2⁺ COMP⁺ PU.1⁺ myofibroblasts, thereby sustaining the vicious cycle of persistent fibrosis in absence of inflammatory triggers. These insights reveal new aspects of fibrosis pathogenesis and highlight biomechanical signals as therapeutic targets in SSc.

Authors with CRIS profile

Ludwig Ueberall Department of Medicine 3 – Rheumatology and Immunology Hashem Mohammadian Department of Medicine 3 – Rheumatology and Immunology Richard Demmler Department of Medicine 3 – Rheumatology and Immunology Yuko Ariza Lehrstuhl für Innere Medizin III Philipp Tripal Optical Imaging Center Erlangen (OICE) Charles Gwellem Anchang Department of Medicine 3 – Rheumatology and Immunology Stefanie Weber Department of Medicine 3 – Rheumatology and Immunology Mario Raphael Angeli Department of Medicine 3 – Rheumatology and Immunology Maria Gabriella Raimondo Department of Medicine 3 – Rheumatology and Immunology Jiyang Chang Department of Medicine 3 – Rheumatology and Immunology Kaiyue Huang Professur für Molekulare Mechanismen der Organfibrose Simon Rauber Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Andreas Ramming Medizinische Fakultät Alina Ramming Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

Universitätsklinikum Düsseldorf

Germany (DE) Universitätsspital Zürich (USZ)

Switzerland (CH)

How to cite

APA:

Ueberall, L., Mohammadian, H., Demmler, R., Ariza, Y., Tripal, P., Anchang, C.G.,... Ramming, A. (2025). Matrix stiffness regulates profibrotic fibroblast differentiation and fibrotic niche activation in systemic sclerosis. Annals of the Rheumatic Diseases. https://doi.org/10.1016/j.ard.2025.05.016

MLA:

Ueberall, Ludwig, et al. "Matrix stiffness regulates profibrotic fibroblast differentiation and fibrotic niche activation in systemic sclerosis." Annals of the Rheumatic Diseases (2025).

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