小柯机器人

Notch信号类风湿关节炎中的作用
2020-04-23 10:40

美国布里格姆妇女医院和哈佛医学院Michael B. BrennerSoumya Raychaudhuri研究团队合作取得新成果。他们发现Notch信号驱动滑膜成纤维细胞特性和关节炎病理。相关论文于2020422日发表于《自然》杂志上。

他们确定NOTCH3信号在表达CD90(由THY1编码)的血管周围和亚层成纤维细胞分化中的关键作用。利用单细胞RNA测序和滑膜组织类器官技术,他们发现NOTCH3信号驱动成纤维细胞中的转录和空间梯度(从血管内皮细胞向外发散)。在活动性类风湿关节炎中,滑膜成纤维细胞中的NOTCH3Notch靶基因明显上调。

在小鼠中,Notch3的基因缺失或NOTCH3信号传导的阻滞可减轻炎症,并预防炎症性关节炎的关节损伤。他们的结果表明,滑膜成纤维细胞表现出由内皮来源的Notch信号调节的位置同一性,并且这种基质串联通路是炎症性关节炎中炎症和病理的基础。

研究人员表示,滑膜是一种间充质组织,主要由成纤维细胞组成,分布在关节的层和亚层中。在类风湿关节炎中,滑膜组织经历明显的增生、发炎和浸润,并损伤关节。最近显示,亚层中的成纤维细胞亚群在类风湿性关节炎中大量的扩增,这与疾病活跃度有关。然而,这些成纤维细胞分化和扩展的分子机制尚不清楚。

附:英文原文

Title: Notch signalling drives synovial fibroblast identity and arthritis pathology

Author: Kevin Wei, Ilya Korsunsky, Jennifer L. Marshall, Anqi Gao, Gerald F. M. Watts, Triin Major, Adam P. Croft, Jordan Watts, Philip E. Blazar, Jeffrey K. Lange, Thomas S. Thornhill, Andrew Filer, Karim Raza, Laura T. Donlin, Christian W. Siebel, Christopher D. Buckley, Soumya Raychaudhuri, Michael B. Brenner

Issue&Volume: 2020-04-22

Abstract: The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3,4,5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients—emanating from vascular endothelial cells outwards—in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.

DOI: 10.1038/s41586-020-2222-z

Source: https://www.nature.com/articles/s41586-020-2222-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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