Mechanophenotype of synovial fibroblasts correlates with patients' pathotypes and treatment response in Rheumatoid Arthritis
- 1Institute for Molecular Systems Engineering and Advanced Materials (IMSEAM), Heidelberg University
Abstract
The mechanical features of synovial fibroblasts may encode clinically relevant information for the management of rheumatoid arthritis. Indeed, it remains poorly understood the links between cellular and microenvironment mechanics with patient stratification and therapeutic response. Here we show that combining organotypic synovial cultures with multimodal mechanophenotyping and transcriptomics identifies distinct ''soft'' and ''stiff'' fibroblast states. Healthy and rheumatoid arthritis fibroblasts were cultured in two or three dimensions (organotypic cell cultures), alone or with endothelial cells, and characterized by high-throughput nanoindentation, picobalance measurements, digital holographic microscopy, Brillouin microscopy and RNA sequencing. Three-dimensional culture reduced single-cell Young's modulus and total mass while increasing dry-mass surface density; endothelial co-culture increased fibroblast stiffness and the longitudinal modulus of intact organotypic cultures. Stiffness-based grouping revealed transcriptional programmes related to extracellular-matrix remodelling, cytoskeletal contractility, and TGF-beta, WNT, and Hippo signalling. Mapping these signatures to publicly available rheumatoid arthritis clinical transcriptomic datasets associated the ''stiff'' state with fibrotic and myeloid-fibrotic pathotypes and treatment-refractory programmes, whereas the ''soft'' state aligned with lymphoid pathotypes and rituximab- or tocilizumab-responsive programmes. These findings support mechanophenotype-associated transcriptional signatures as potential biomarkers for rheumatoid arthritis stratification.
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BibTeX
@misc{diaz2026mechanophenotype,
title = {{Mechanophenotype of synovial fibroblasts correlates with patients' pathotypes and treatment response in Rheumatoid Arthritis}},
author = {F. Diaz and T. Debatin and L. Messner and C. Mouchel dit Grainville and J. Andres and F. Riethmuller and R. Vaishampayan Vikrant and R. Fronza and F. Taheri and Z. Wang and C. Selhuber-Unkel and F. Colombo},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755901},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755901v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Mechanophenotype of synovial fibroblasts correlates with patients' pathotypes and treatment response in Rheumatoid Arthritis
AU - F. Diaz
AU - T. Debatin
AU - L. Messner
AU - C. Mouchel dit Grainville
AU - J. Andres
AU - F. Riethmuller
AU - R. Vaishampayan Vikrant
AU - R. Fronza
AU - F. Taheri
AU - Z. Wang
AU - C. Selhuber-Unkel
AU - F. Colombo
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755901
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755901v1
AB - The mechanical features of synovial fibroblasts may encode clinically relevant information for the management of rheumatoid arthritis. Indeed, it remains poorly understood the links between cellular and microenvironment mechanics with patient stratification and therapeutic response. Here we show that combining organotypic synovial cultures with multimodal mechanophenotyping and transcriptomics identifies distinct ''soft'' and ''stiff'' fibroblast states. Healthy and rheumatoid arthritis fibroblasts were cultured in two or three dimensions (organotypic cell cultures), alone or with endothelial cells, and characterized by high-throughput nanoindentation, picobalance measurements, digital holographic microscopy, Brillouin microscopy and RNA sequencing. Three-dimensional culture reduced single-cell Young's modulus and total mass while increasing dry-mass surface density; endothelial co-culture increased fibroblast stiffness and the longitudinal modulus of intact organotypic cultures. Stiffness-based grouping revealed transcriptional programmes related to extracellular-matrix remodelling, cytoskeletal contractility, and TGF-beta, WNT, and Hippo signalling. Mapping these signatures to publicly available rheumatoid arthritis clinical transcriptomic datasets associated the ''stiff'' state with fibrotic and myeloid-fibrotic pathotypes and treatment-refractory programmes, whereas the ''soft'' state aligned with lymphoid pathotypes and rituximab- or tocilizumab-responsive programmes. These findings support mechanophenotype-associated transcriptional signatures as potential biomarkers for rheumatoid arthritis stratification.
ER -