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Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

ABSTRACT: Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

PROVIDER: PRJNA531402 | ENA |

REPOSITORIES: ENA

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Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

Project description:Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

| PRJNA530021 | ENA

Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

Project description:The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune mediated inflammatory diseases (IMIDs). Yet, despite their key role in disease, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue driven pathologies observed in IMIDs such as inflammation and damage . Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of FAPa+ synovial cells suppressed both inflammation and bone erosions in murine models of resolving and persistent arthritis. Single cell transcriptional analysis identified two distinct fibroblast subsets: FAPa+ THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPa+ THY1- destructive fibroblasts restricted to the synovial lining. When adoptively transferred into the joint, FAPa+ THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation whereas transfer of FAPa+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell based therapies aimed at modulating inflammation and tissue damage.

2019-04-09 | GSE129451 | GEO

Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

2019-06-03 | GSE129087 | GEO

Distinct fibroblast subsets drive inflammation and damage in arthritis.

Project description: Not available

| S-EPMC6690841 | biostudies-literature

Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

Project description:Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

| PRJNA430903 | ENA

Pathologically expanded peripheral B cell-helper T cells in rheumatoid arthritis

Project description:Pathologically expanded peripheral B cell-helper T cells in rheumatoid arthritis

| PRJNA359141 | ENA

RNA-seq analysis of freshly isolated synovial fibroblast subsets from patients with rheumatoid arthritis

Project description:Transcriptomics of distinct subpopulations of synovial fibroblasts from osteoarthritis and rheumatoid arthritis arthroplasty tissues.

2018-01-19 | GSE109448 | GEO

Microarray analysis of freshly isolated synovial fibroblast subsets in patients with rheumatoid arthritis or osteoarthritis

Project description:Transcriptomics of distinct subpopulations of synovial fibroblasts from osteoarthritis and rheumatoid arthritis arthroplasty tissues.

2018-01-17 | GSE107105 | GEO

RNA-seq analysis of freshly isolated synovial fibroblast subsets from patients with rheumatoid arthritis

Project description:RNA-seq analysis of freshly isolated synovial fibroblast subsets from patients with rheumatoid arthritis

| PRJNA430901 | ENA

miR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis

Project description:MicroRNAs (miRNAs) constitute fine tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA), however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. We have shown in the past that the expression of the miR-221/222 cluster is upregulated in RA SFs. Here, we demonstrate that miR-221/222 activation is downstream of major inflammatory cytokines, such as TNF and IL-1β, which promote miR-221/222 expression independently. miR-221/222 expression in SFs from the huTNFtg mouse model of arthritis correlates with disease progression. Targeted transgenic overexpression of miR-221/222 in SFs of the huTNFtg mouse model led to further expansion of synovial fibroblasts and disease exacerbation. miR-221/222 overexpression altered the transcriptional profile of SFs igniting pathways involved in cell cycle progression and ECM regulation. Validated targets of miR-221/222 included p27 and p57 cell cycle inhibitors, as well as Smarca1 (a chromatin remodeling component). In contrast, complete genetic ablation of miR-221/222 in arthritic mice led to decreased proliferation of fibroblasts, reduced synovial expansion and attenuated disease. scATAC-seq data analysis revealed increased miR-221/222 gene activity in the pathogenic and activated clusters of the intermediate and lining compartment. Taken together, our results establish an SF-specific pathogenic role of the miR-221/222 cluster in arthritis and suggest that its therapeutic targeting in specific subpopulations should inform the design of novel fibroblast-targeted therapies for human disease.

2022-12-16 | GSE210887 | GEO

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