Fibroblast-like synoviocytes (FLS) play a crucial role in JIA pathogenesis; however, the mechanisms by which they contribute to disease progression are not well described. Previous studies demonstrated that rheumatoid arthritis FLS are heterogeneous, and subpopulations with transformed, aggressive phenotypes cause invasive and destructive disease activity. We employ single-cell RNA-sequencing (scRNA-seq) to investigate JIA FLS heterogeneity and gene expression that distinguishes JIA subtypes. JIA FLS cell lines from three persistent oligoarticular, three pre-extension oligoarticular, and three polyarticular subtypes were cultured. scRNA-seq was performed by Genewiz according to 10 × Genomics Chromium protocols. SeuratR package was used for QC, analysis, and exploration of data. FLS are heterogeneous and have characteristics of fibroblasts, chondrocytes, and smooth muscle cells. The chondrocyte-like subpopulation is the predominant cell type and percentages of this subpopulation increase with disease severity. Despite overlapping subpopulations, the chondrocyte-like cells have unique genetic fingerprints that distinguish between JIA subtypes. LRRC15, GREM1, and GREM2 are overexpressed in chondrocyte-like cells from persistent oligoarticular JIA FLS compared to pre-extension oligoarticular JIA FLS. S100A4, TIMP3, and NBL1 are overexpressed in pre-extension oligoarticular JIA FLS compared to polyarticular JIA FLS. CRLF1, MFAP5, and TNXB are overexpressed in persistent oligoarticular JIA FLS compared to polyarticular JIA FLS. We found biologically relevant differences in gene expression between JIA subtypes that support a critical role for FLS in pathogenesis. We also demonstrate that gene expression within the chondrocyte-like subpopulation can be used to distinguish between these subtypes.

中文翻译：

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单细胞分析揭示幼年特发性关节炎成纤维细胞样滑膜细胞的异质性对疾病亚型的影响

成纤维细胞样滑膜细胞 (FLS) 在 JIA 发病机制中起着至关重要的作用；然而，它们促进疾病进展的机制并未得到很好的描述。以前的研究表明，类风湿性关节炎 FLS 是异质的，具有转化的、侵袭性表型的亚群会导致侵入性和破坏性的疾病活动。我们采用单细胞 RNA 测序 (scRNA-seq) 来研究 JIA FLS 异质性和区分 JIA 亚型的基因表达。培养了来自三种持久性寡关节、三种延伸前寡关节和三种多关节亚型的 JIA FLS 细胞系。scRNA-seq 由 Genewiz 根据 10 × Genomics Chromium 协议进行。SeuratR 包用于 QC、分析和数据探索。FLS是异质的，具有成纤维细胞的特征，软骨细胞和平滑肌细胞。软骨细胞样亚群是主要的细胞类型，并且该亚群的百分比随着疾病的严重程度而增加。尽管亚群重叠，但软骨细胞样细胞具有区分 JIA 亚型的独特遗传指纹。与延伸前少关节 JIA FLS 相比，LRRC15、GREM1 和 GREM2 在来自持续性少关节 JIA FLS 的软骨细胞样细胞中过表达。与多关节 JIA FLS 相比，S100A4、TIMP3 和 NBL1 在前伸少关节 JIA FLS 中过表达。与多关节 JIA FLS 相比，CRLF1、MFAP5 和 TNXB 在持续性少关节 JIA FLS 中过表达。我们发现 JIA 亚型之间基因表达的生物学相关差异支持 FLS 在发病机制中的关键作用。