Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

Area of Science:

• Immunology
• Cell Biology
• Rheumatology

Background:

• Fibroblasts are crucial for tissue homeostasis, inflammation, and repair.
• In rheumatoid arthritis (RA), synovial fibroblasts drive chronic inflammation and joint destruction.
• Fibroblast heterogeneity and its role in RA pathology remain largely unexplored.

Purpose of the Study:

• To investigate fibroblast heterogeneity in human synovial tissues.
• To identify distinct fibroblast subsets and their potential roles in rheumatoid arthritis (RA).
• To characterize pathogenic fibroblast subsets in RA and osteoarthritis (OA).

Main Methods:

• Utilized bulk transcriptomics of targeted fibroblast subpopulations.
• Employed single-cell transcriptomics for high-resolution analysis.
• Integrated transcriptomic data to define fibroblast subsets based on surface protein phenotypes.

Main Results:

• Identified seven distinct fibroblast subsets with unique surface protein markers.
• Integrated data revealed three main fibroblast subsets.
• One subset, marked by podoplanin, THY1, and cadherin-11 (and CD34-negative), was threefold expanded in RA patients compared to OA patients.
• This RA-associated fibroblast subset resides in the perivascular zone, secretes pro-inflammatory cytokines, is proliferative, and displays invasive characteristics in vitro.

Conclusions:

• Fibroblast heterogeneity exists in human synovial tissue.
• A specific fibroblast subset is expanded and pathogenic in rheumatoid arthritis (RA).
• This subset contributes to RA-driven joint inflammation and destruction.
• The employed strategy can identify pathogenic stromal cell subsets in other complex diseases.