Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis

Abstract

ObjectivesTo integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis.MethodsIn this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed.ResultsWe identified four SF clusters with respective marker genes: PRG4+ SF (CD55, MMP3, PRG4, THY1neg); CXCL12+ SF (CXCL12, CCL2, ADAMTS1, THY1low); POSTN+ SF (POSTN, collagen genes, THY1); CXCL14+ SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4+ SF) and sublining (CXCL12+ SF, POSTN+ + and CXCL14+ SF) SF subsets. CXCL12+ SF and POSTN+ + were most prominent in the fibroid while PRG4+ SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4+ SF correlated positively with disease severity parameters in the fibroid, POSTN+ SF in the lymphoid pathotype whereas CXCL14+ SF showed negative association with disease severity in all pathotypes.ConclusionThis study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.

Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go?

“…), which could significantly decrease the off-target effects of FLS-based treatments 85. In a recently published paper, the different FLS subsets have been associated with distinct clinical and laboratory alterations, raising the possibility of FLS-based personalized treatments in the future 86. So far, however, there are no well-working FLS-specific therapies in RA and several of the above-mentioned therapeutic approaches can modify the function of other cell types, as well.…”

The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis

“…These cells are involved differently in the pathogenesis of RA. They differ in their gene expression patterns, cellular markers and epigenetic signature (14,15,33). The synovium also houses mesenchymal stem cells (MSC).…”

Inside the Joint of Inflammatory Arthritis Patients: Handling and Processing of Synovial Tissue Biopsies for High Throughput Analysis

“…While identification and characterization of cell types and populations that associate with aspects of synovial pathology in arthritis, further characterization of the communication between synovial cell populations is needed. Altered distribution of synovial fibroblast subsets between distinct disease pathotypes characterized by differential immune cell composition, highlights that disease pathotypes are characterized by potentially unique immune-fibroblast cell interaction pathways ( 101 ). Further studies that incorporate scRNAseq and spatial transcriptomic analysis will elucidate cell-cell interactions and their connection to distinct arthritis pathotypes.…”