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Stromal cell subtypes define distinct pathogenesis in RA and PsA

Inflammatory Arthritis (IA) is characterised by neoangiogenesis, leukocyte infiltration, the release of pro-inflammatory mediators and activation of synovial fibroblasts (FLS), which leads to cartilage/bone damage and subsequent joint destruction. Two of the most common forms of IA are rheumatoid arthritis (RA) and psoriatic Arthritis (PsA). Common pathogenic features exist between RA and PsA, however significant differences are observed at the clinical, immunological, cellular and molecular levels. At the site of inflammation (the synovium), we and others have demonstrated significant differences in the vasculature, immune-cell infiltrates and the invasive lining-layer, which may be associated with the distinct pattern of joint involvement and bone erosion observed. Common and distinct responses to targeted therapies have also been demonstrated. At a molecular single-cell level little is known about the distinct underlying mechanisms involved in driving this differential pathogenesis in the target tissue of disease with most studies restricted to histological-analysis. Using advanced flow-cytometry and single-cell RNAseq of RA and PsA synovial cell suspensions, our preliminary data has demonstrated distinct differences in FLS populations, with significantly higher frequency of CD34-PDPN+THY1+ FLS vs CD34-PDPN+Thy1- FLS observed in RA, in contrast to enrichment of CD34-FAPα+THY1- FLS in PsA. While we have shown differences in the effect of expanded RA vs PsA FLS on endothelial cell function and osteoclastogenesis, little is known about the distinct functional role of these FLS population in RA vs PsA with regards to the regulation of inflammatory pathways, immune effector cell function and to cartilage/bone damage. Therefore in this project, using scRNAseq, VISIUM spatial-RNAseq, non-invasive FLIM analysis, along with extensive mechanistic studies using 2D/3D culture models, and ‘Joint-on-chip’ models we will dissect the distinct molecular signatures of FLS subtypes from RA and PsA to define (i) differential pathogenic mechanisms, (ii) disease progression/response and (iii) identify new targets for novel therapeutic strategies.