Notch signalling drives synovial fibroblast identity and arthritis pathology.
Kevin WeiIlya KorsunskyJennifer L MarshallAnqi GaoGerald F M WattsTriin MajorAdam P CroftJordan WattsPhilip E BlazarJeffrey K LangeThomas S ThornhillAndrew FilerKarim RazaLaura T Donlinnull nullChristian W SiebelChristopher Dominic BuckleySoumya RaychaudhuriMichael B BrennerPublished in: Nature (2020)
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 activity3-5; 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.
Keyphrases
- rheumatoid arthritis
- disease activity
- cell proliferation
- extracellular matrix
- oxidative stress
- single cell
- ankylosing spondylitis
- systemic lupus erythematosus
- endothelial cells
- rheumatoid arthritis patients
- interstitial lung disease
- nitric oxide
- genome wide
- dna methylation
- bone marrow
- transcription factor
- systemic sclerosis
- rna seq
- high throughput
- copy number
- skeletal muscle