Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

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, John Wright, Barry P. Simmons, Laura T. Donlin, George D. Kalliolias, Susan M. Goodman, Vivian P. Bykerk, Lionel B. Ivashkiv, James A. Lederer, Nir Hacohen, Peter A. Nigrovic, Andrew Filer, Christopher D. Buckley, Soumya Raychaudhuri () and Michael B. Brenner ()
Additional contact information
Fumitaka Mizoguchi: Harvard Medical School
Kamil Slowikowski: 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
Hung N. Nguyen: Harvard Medical School
Erika H. Noss: Harvard Medical School
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
George D. Kalliolias: Hospital for Special Surgery
Susan M. Goodman: Hospital for Special Surgery
Vivian P. Bykerk: Hospital for Special Surgery
Lionel B. Ivashkiv: Hospital for Special Surgery
James A. Lederer: Brigham and Women’s Hospital and Harvard Medical School
Nir Hacohen: Broad Institute of MIT and Harvard
Peter A. Nigrovic: Harvard Medical School
Andrew Filer: Queen Elizabeth Hospital
Christopher D. Buckley: Queen Elizabeth Hospital
Soumya Raychaudhuri: Harvard Medical School
Michael B. Brenner: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02892-y

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