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Notch signalling drives synovial fibroblast identity and arthritis pathology

Author

Listed:
  • Kevin Wei

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Ilya Korsunsky

    (Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital
    Brigham and Women’s Hospital
    Harvard Medical School)

  • Jennifer L. Marshall

    (University of Birmingham, Queen Elizabeth Hospital)

  • Anqi Gao

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Gerald F. M. Watts

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Triin Major

    (University of Birmingham, Queen Elizabeth Hospital)

  • Adam P. Croft

    (University of Birmingham, Queen Elizabeth Hospital)

  • Jordan Watts

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Philip E. Blazar

    (Brigham and Women’s Hospital)

  • Jeffrey K. Lange

    (Brigham and Women’s Hospital)

  • Thomas S. Thornhill

    (Brigham and Women’s Hospital)

  • Andrew Filer

    (University of Birmingham, Queen Elizabeth Hospital)

  • Karim Raza

    (University of Birmingham, Queen Elizabeth Hospital)

  • Laura T. Donlin

    (Hospital for Special Surgery)

  • Christian W. Siebel

    (Genentech)

  • Christopher D. Buckley

    (University of Birmingham, Queen Elizabeth Hospital
    University of Oxford)

  • Soumya Raychaudhuri

    (Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital
    Brigham and Women’s Hospital
    Harvard Medical School)

  • Michael B. Brenner

    (Brigham and Women’s Hospital and Harvard Medical School)

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 activity3–5; 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.

Suggested Citation

  • 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 File, 2020. "Notch signalling drives synovial fibroblast identity and arthritis pathology," Nature, Nature, vol. 582(7811), pages 259-264, June.
  • Handle: RePEc:nat:nature:v:582:y:2020:i:7811:d:10.1038_s41586-020-2222-z
    DOI: 10.1038/s41586-020-2222-z
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    Citations

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    Cited by:

    1. Joyce B. Kang & Aparna Nathan & Kathryn Weinand & Fan Zhang & Nghia Millard & Laurie Rumker & D. Branch Moody & Ilya Korsunsky & Soumya Raychaudhuri, 2021. "Efficient and precise single-cell reference atlas mapping with Symphony," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    2. Muriel Elhai & Raphael Micheroli & Miranda Houtman & Masoumeh Mirrahimi & Larissa Moser & Chantal Pauli & Kristina Bürki & Andrea Laimbacher & Gabriela Kania & Kerstin Klein & Philipp Schätzle & Mojca, 2023. "The long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Kathryn Weinand & Saori Sakaue & Aparna Nathan & Anna Helena Jonsson & Fan Zhang & Gerald F. M. Watts & Majd Al Suqri & Zhu Zhu & Deepak A. Rao & Jennifer H. Anolik & Michael B. Brenner & Laura T. Don, 2024. "The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    4. Meiling Zheng & Zhi Hu & Xiaole Mei & Lianlian Ouyang & Yang Song & Wenhui Zhou & Yi Kong & Ruifang Wu & Shijia Rao & Hai Long & Wei Shi & Hui Jing & Shuang Lu & Haijing Wu & Sujie Jia & Qianjin Lu & , 2022. "Single-cell sequencing shows cellular heterogeneity of cutaneous lesions in lupus erythematosus," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Ruiye Bi & Qing Yin & Haohan Li & Xianni Yang & Yiru Wang & Qianli Li & Han Fang & Peiran Li & Ping Lyu & Yi Fan & Binbin Ying & Songsong Zhu, 2023. "A single-cell transcriptional atlas reveals resident progenitor cell niche functions in TMJ disc development and injury," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Michael T. H. Ng & Rowie Borst & Hamez Gacaferi & Sarah Davidson & Jessica E. Ackerman & Peter A. Johnson & Caio C. Machado & Ian Reekie & Moustafa Attar & Dylan Windell & Mariola Kurowska-Stolarska &, 2024. "A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    7. Alessandra Nerviani & Marie-Astrid Boutet & Giulia Maria Ghirardi & Katriona Goldmann & Elisabetta Sciacca & Felice Rivellese & Elena Pontarini & Edoardo Prediletto & Federico Abatecola & Mattia Calis, 2024. "Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022. "Identification, discrimination and heterogeneity of fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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