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Nat Commun. 2018 Feb 23;9(1):789. doi: 10.1038/s41467-018-02892-y.

Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis.

Author information

1
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
2
Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8519, Japan.
3
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02446, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
5
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA, 02138, USA.
6
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA.
7
Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK.
8
JW Creagene Corporation, Seongnam-Si, 13202, South Korea.
9
Division of Rheumatology, University of Washington, Seattle, WA, 98109, USA.
10
Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA.
11
Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, 10021, USA.
12
Weill Cornell Graduate School of Medical Sciences, New York, NY, 10021, USA.
13
Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
14
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA, 02114, USA.
15
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
16
Division of Immunology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
17
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. soumya@broadinstitute.org.
18
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02446, USA. soumya@broadinstitute.org.
19
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. soumya@broadinstitute.org.
20
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA. soumya@broadinstitute.org.
21
Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK. soumya@broadinstitute.org.
22
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. mbrenner@research.bwh.harvard.edu.

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.

PMID:
29476097
PMCID:
PMC5824882
DOI:
10.1038/s41467-018-02892-y
[Indexed for MEDLINE]
Free PMC Article

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