Cross-species single-cell and spatial transcriptomics map the conserved stromal remodeling landscape of inflammatory arthritis.
- 1Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States.
Abstract
Background
Rheumatoid arthritis (RA) is a condition characterized by chronic synovial inflammation and joint destruction. However, the precise networks linking cellular activation to stromal-mediated pathology remain poorly defined, hindering the development of targeted therapies.Methods
We integrated single-cell RNA sequencing (scRNA-seq) across multiple preclinical mouse models to construct a unified synovial inflammatory arthritis landscape, later validating our findings in a human RA dataset using Visium HD spatial transcriptomics.Results
Unsupervised clustering of the mouse synovium resolved distinct structural, vascular, and immune niches. Interactome mapping identified Vascular Mural cells as central hubs receiving endothelial- and mural-derived Notch signaling. Downstream of this perivascular trigger, regulatory network analysis revealed a synchronized, stress-induced Atf3/Fos (AP-1) transcription factor regulon program coordinating myofibroblast differentiation. This pathway is conserved in human RA; a homologous matrix-remodeling gene expression module (SM01, including VIM, FN1, MMP2) was highly active in human Activated FLS and Lining FLS. Visium HD spatial mapping physically positioned these circuitries, demonstrating that FN1 and THBS signaling networks co-localized in a highly active niche restricted to the synovial tissue's edge.Conclusion
We define a conserved Notch/AP-1 to Fn1/THBS module regulatory axis operating within a distinct spatial niche. This model moves beyond traditional cellular profiling to identify therapeutic targets potentially useful towards simultaneously halting synovial inflammation and joint destruction.
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BibTeX
@article{figueiredo2026crossspecies,
title = {{Cross-species single-cell and spatial transcriptomics map the conserved stromal remodeling landscape of inflammatory arthritis.}},
author = {Marxa L Figueiredo},
journal = {Frontiers in molecular medicine},
year = {2026},
month = oct,
doi = {10.3389/fmmed.2026.1951540},
url = {https://europepmc.org/article/MED/43011835},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cross-species single-cell and spatial transcriptomics map the conserved stromal remodeling landscape of inflammatory arthritis.
AU - Marxa L Figueiredo
PY - 2026
DA - 2026/10/19
JO - Frontiers in molecular medicine
DO - 10.3389/fmmed.2026.1951540
UR - https://europepmc.org/article/MED/43011835
AB - Background Rheumatoid arthritis (RA) is a condition characterized by chronic synovial inflammation and joint destruction. However, the precise networks linking cellular activation to stromal-mediated pathology remain poorly defined, hindering the development of targeted therapies.Methods We integrated single-cell RNA sequencing (scRNA-seq) across multiple preclinical mouse models to construct a unified synovial inflammatory arthritis landscape, later validating our findings in a human RA dataset using Visium HD spatial transcriptomics.Results Unsupervised clustering of the mouse synovium resolved distinct structural, vascular, and immune niches. Interactome mapping identified Vascular Mural cells as central hubs receiving endothelial- and mural-derived Notch signaling. Downstream of this perivascular trigger, regulatory network analysis revealed a synchronized, stress-induced Atf3/Fos (AP-1) transcription factor regulon program coordinating myofibroblast differentiation. This pathway is conserved in human RA; a homologous matrix-remodeling gene expression module (SM01, including VIM, FN1, MMP2) was highly active in human Activated FLS and Lining FLS. Visium HD spatial mapping physically positioned these circuitries, demonstrating that FN1 and THBS signaling networks co-localized in a highly active niche restricted to the synovial tissue's edge.Conclusion We define a conserved Notch/AP-1 to Fn1/THBS module regulatory axis operating within a distinct spatial niche. This model moves beyond traditional cellular profiling to identify therapeutic targets potentially useful towards simultaneously halting synovial inflammation and joint destruction.
SN - 2674-0095
ER -