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Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

Author

Listed:
  • Fumitaka Mizoguchi

    (Harvard Medical School
    Tokyo Medical and Dental University (TMDU))

  • Kamil Slowikowski

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard University
    Harvard Medical School)

  • Kevin Wei

    (Harvard Medical School)

  • Jennifer L. Marshall

    (Queen Elizabeth Hospital)

  • Deepak A. Rao

    (Harvard Medical School)

  • Sook Kyung Chang

    (Harvard Medical School
    JW Creagene Corporation)

  • Hung N. Nguyen

    (Harvard Medical School)

  • Erika H. Noss

    (Harvard Medical School
    University of Washington)

  • Jason D. Turner

    (Queen Elizabeth Hospital)

  • Brandon E. Earp

    (Brigham and Women’s Hospital)

  • Philip E. Blazar

    (Brigham and Women’s Hospital)

  • John Wright

    (Brigham and Women’s Hospital)

  • Barry P. Simmons

    (Brigham and Women’s Hospital)

  • Laura T. Donlin

    (Hospital for Special Surgery
    Weill Cornell Graduate School of Medical Sciences)

  • George D. Kalliolias

    (Hospital for Special Surgery)

  • Susan M. Goodman

    (Hospital for Special Surgery
    Weill Cornell Graduate School of Medical Sciences)

  • Vivian P. Bykerk

    (Hospital for Special Surgery
    Weill Cornell Graduate School of Medical Sciences)

  • Lionel B. Ivashkiv

    (Hospital for Special Surgery
    Weill Cornell Graduate School of Medical Sciences)

  • James A. Lederer

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

  • Nir Hacohen

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Peter A. Nigrovic

    (Harvard Medical School
    Harvard Medical School)

  • Andrew Filer

    (Queen Elizabeth Hospital)

  • Christopher D. Buckley

    (Queen Elizabeth Hospital)

  • Soumya Raychaudhuri

    (Harvard Medical School
    Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Michael B. Brenner

    (Harvard Medical School)

Abstract

Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.

Suggested Citation

  • Fumitaka Mizoguchi & Kamil Slowikowski & Kevin Wei & Jennifer L. Marshall & Deepak A. Rao & Sook Kyung Chang & Hung N. Nguyen & Erika H. Noss & Jason D. Turner & Brandon E. Earp & Philip E. Blazar & J, 2018. "Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02892-y
    DOI: 10.1038/s41467-018-02892-y
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    Cited by:

    1. 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.
    2. Nabangshu Das & Luiz G. N. Almeida & Afshin Derakhshani & Daniel Young & Kobra Mehdinejadiani & Paul Salo & Alexander Rezansoff & Gregory D. Jay & Christian P. Sommerhoff & Tannin A. Schmidt & Roman K, 2023. "Tryptase β regulation of joint lubrication and inflammation via proteoglycan-4 in osteoarthritis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Samira Abbasgholizadeh Rahimi & Mojtaba Kolahdoozi & Arka Mitra & Jose L. Salmeron & Amir Mohammad Navali & Alireza Sadeghpour & Seyed Amir Mir Mohammadi, 2022. "Quantum-Inspired Interpretable AI-Empowered Decision Support System for Detection of Early-Stage Rheumatoid Arthritis in Primary Care Using Scarce Dataset," Mathematics, MDPI, vol. 10(3), pages 1-19, February.
    4. Niki Karagianni & Ksanthi Kranidioti & Nikolaos Fikas & Maria Tsochatzidou & Panagiotis Chouvardas & Maria C Denis & George Kollias & Christoforos Nikolaou, 2019. "An integrative transcriptome analysis framework for drug efficacy and similarity reveals drug-specific signatures of anti-TNF treatment in a mouse model of inflammatory polyarthritis," PLOS Computational Biology, Public Library of Science, vol. 15(5), pages 1-25, May.

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