Annals of the rheumatic diseases · 2026
RA and PsA synovial tissue single-cell analysis demonstrates differential fibroblast populations with distinct phenotypes and functional capacities.
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Tynan Órla, Brugman Aenea A I, Smith Conor M, Canavan Mary, O'Rourke Aoife M, Floudas Achilleas, Anton Dumitru, Wade Siobhán, Sundanum Sonia, Fletcher Jean M, Orr Carl, Veale Douglas J, Fearon Ursula
Аннотация
OBJECTIVES: This study determines the phenotypic and functional characteristics that define distinct fibroblast-like synoviocyte (FLS) populations in rheumatoid arthritis (RA) vs psoriatic arthritis (PsA).
METHODS: Single-cell RNA sequencing and multiparametric flow cytometry analysis (21 markers) were performed on RA and PsA synovial cell suspensions to determine FLS phenotype/function. Podoplanin (PDPN)+ FLS and sorted THY1+ FLS vs THY1⁻ FLS function in RA vs PsA was assessed by flow cytometry, enzyme-linked immunosorbent assay (ELISA), quantitative real -time quantitative polymerase chain reaction (qPCR), and metabolic analysis ex vivo, in vitro, and in the presence of verteporfin (Hippo signalling blockade).
RESULTS: Flow analysis of PDPN+ FLS demonstrated significant increases in human leukocyte antigen (HLA)-DR+, yes-associated protein (YAP)+, cadherin 11 (Cad11)+, and phosphorylated protein S6+ FLS in RA (all P < .05), while CD55 was increased in PsA-FLS (P < .001). Polyfunctionality demonstrated enhanced coexpression of Cad11+CD44+HLA-DR+ICAM-1+ FLS (P < .01) and CD44+HLA-DR+ICAM-1+VCAM-1+ FLS (P < .05) in RA, whereas PsA-FLS exhibited increased coexpression of pAKT+pmTOR+ (P < .01). THY1+ FLS populations were dominant in RA (P < .05), while THY1⁻ FLS were dominant in PsA (P < .05), with differential angiogenic, chemokine, and matrix metalloproteinase expression observed. THY1+FAP+ FLS correlated with disease activity score (DAS28) (r = 0.55, P < .05) and synovitis (r = 0.54, P < .05). Further flow analysis identified 6 main distinct FLS populations, with enrichment of THY1+CD34⁻CD55⁻FAP+ FLS and THY1+CD34+CD55⁻FAP+ FLS in RA (P < .05), while PsA displayed enrichment of THY1+CD34-CD55+FAP+ FLS (P < .05) and THY1⁻CD34⁻CD55+FAP+ FLS (P < .001). Immune/adhesive markers were significantly higher in RA subpopulations, whereas metabolic/osteogenic markers were higher in PsA subpopulations. ScRNA-seq identified 16 distinct FLS clusters, with 3 sublining clusters enriched in RA compared with PsA, including THY1hiPOSTN+, THY1hiCXCL12+CHI3L2+, and THY1hiCXCL12+APOE+. Pathway enrichment analysis identified heightened Hippo signalling in RA THY1hiPOSTN+ FLS, and blockade of this signalling inhibited FLS pathogenic function.
CONCLUSIONS: RA and PsA possess distinct FLS populations with unique functional and metabolic properties, which may facilitate improved understanding of disease pathogenesis and therapeutic response.
METHODS: Single-cell RNA sequencing and multiparametric flow cytometry analysis (21 markers) were performed on RA and PsA synovial cell suspensions to determine FLS phenotype/function. Podoplanin (PDPN)+ FLS and sorted THY1+ FLS vs THY1⁻ FLS function in RA vs PsA was assessed by flow cytometry, enzyme-linked immunosorbent assay (ELISA), quantitative real -time quantitative polymerase chain reaction (qPCR), and metabolic analysis ex vivo, in vitro, and in the presence of verteporfin (Hippo signalling blockade).
RESULTS: Flow analysis of PDPN+ FLS demonstrated significant increases in human leukocyte antigen (HLA)-DR+, yes-associated protein (YAP)+, cadherin 11 (Cad11)+, and phosphorylated protein S6+ FLS in RA (all P < .05), while CD55 was increased in PsA-FLS (P < .001). Polyfunctionality demonstrated enhanced coexpression of Cad11+CD44+HLA-DR+ICAM-1+ FLS (P < .01) and CD44+HLA-DR+ICAM-1+VCAM-1+ FLS (P < .05) in RA, whereas PsA-FLS exhibited increased coexpression of pAKT+pmTOR+ (P < .01). THY1+ FLS populations were dominant in RA (P < .05), while THY1⁻ FLS were dominant in PsA (P < .05), with differential angiogenic, chemokine, and matrix metalloproteinase expression observed. THY1+FAP+ FLS correlated with disease activity score (DAS28) (r = 0.55, P < .05) and synovitis (r = 0.54, P < .05). Further flow analysis identified 6 main distinct FLS populations, with enrichment of THY1+CD34⁻CD55⁻FAP+ FLS and THY1+CD34+CD55⁻FAP+ FLS in RA (P < .05), while PsA displayed enrichment of THY1+CD34-CD55+FAP+ FLS (P < .05) and THY1⁻CD34⁻CD55+FAP+ FLS (P < .001). Immune/adhesive markers were significantly higher in RA subpopulations, whereas metabolic/osteogenic markers were higher in PsA subpopulations. ScRNA-seq identified 16 distinct FLS clusters, with 3 sublining clusters enriched in RA compared with PsA, including THY1hiPOSTN+, THY1hiCXCL12+CHI3L2+, and THY1hiCXCL12+APOE+. Pathway enrichment analysis identified heightened Hippo signalling in RA THY1hiPOSTN+ FLS, and blockade of this signalling inhibited FLS pathogenic function.
CONCLUSIONS: RA and PsA possess distinct FLS populations with unique functional and metabolic properties, which may facilitate improved understanding of disease pathogenesis and therapeutic response.