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Single cell RNA sequencing on synovium, meniscus and cartilage of rheumatoid arthritis

ABSTRACT: Rheumatoid arthritis (RA) induced destruction of knee joints is a common cause of total knee arthroplasty (TKA). Under single cell RNA sequencing generated by 10x Genomics, we identified CD142+ synovial fibroblasts as a novel cluster, located at the sublining layer in normal and osteoarthritis knee synovium, but elevated and distributed at the lining layer in RA knee synovium, and infiltrated in multiple RA joint synovia. Intra-articular injection of CD142+ synovial fibroblasts can quickly and drastically damage the meniscus but has a slight effect on cartilage.Long-term follow-up of the RA cohort indicated that enriched CD142+ synovial fibroblasts in the lining layer was a risk factor for severe joint destruction and eventually underwent TKA. Our results demonstrate that CD142+ synovial fibroblasts can be used as an indicator to assess prognosis and a therapeutic target to inhibit meniscal damage, thereby alleviating RA knee joint destruction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299518 | GEO | 2025/06/17

REPOSITORIES: GEO

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Project description:Purposes Recurrent synovial bleeding is the major cause of Hemophilic Arthritis (HA). Up to now, the transcriptomic profiles of bleeding syvonium in HA patient have largely remained unknown. Exploring the transcriptomic characteristics of synovium obtained from HA patients undergoing total knee arthroplasty (TKA), and uncovering potential pathological mechanisms of HA synovium through bioinformatics analysis and differential analysis. Methods Single-cell RNA sequencing (scRNA-seq) technology was utilized to identify distinct cellular subsets within HA synovium. Comparative analysis was conducted with scRNA-seq data from osteoarthritis (OA) and rheumatoid arthritis (RA) synovium to assess transcriptional differences. Histological evaluation, immunofluorescence (IF), immunohistochemistry (IHC) and in vitro cell testing were performed for validation. Results We observed that the single-cell transcriptomic characteristics of HA synovium differ significantly from those of OA and RA patients. Mast cells, identified as unique immune cells in HA synovium, are actively involved and may be the initiating factor for changes in vascular permeability or bleeding in HA synovium. The transcriptomic features of endothelial cells and fibroblasts, which are non-immune stromal cells, reveal the synovial microenvironment: repeated bleeding leads to iron deposition, which causes substantial ferroptosis within the synovium. Based on the pseudotime analysis of endothelial cells, along with IHC staining and in vitro cell assays, it was demonstrated that ferroptosis in endothelial cells induces vascular damage and triggers a significant migration of endothelial cells. The stress of ferroptosis leads to the differentiation of HMOX1+ endothelial cells. Cell interaction analysis shows that HMOX1+ endothelial cells can induce the SCARA5+ fibroblast subtypes via FTL/SCARA5. This may be a critical target for alleviating cellular ferroptosis in HA synovium. Conclusions Through scRNA-seq, we elucidated the heterogeneity of synovial tissues in three diseases. Activated mast cells around blood vessels may be potential target cells for bleeding and rebleeding, with TPSB2 emerging as a potential target. We also identified endothelial cell subpopulations under ferroptosis stress and their interactions with fibroblasts. Notably, we discovered a SCARA5+ fibroblast subpopulation that regulates ferroptosis, which could serve as a potential target gene for preventing and treating recurrent bleeding in HA.

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Single cell RNA sequencing on synovium, meniscus and cartilage of rheumatoid arthritis

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