Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-02892-y
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Funding
- Ruth L. Kirschstein National Research Service Award from National Institute of Arthritis and Musculoskeletal and Skin Diseases [F31AR070582]
- Rheumatology Research Foundation
- NIH Arthritis and Musculoskeletal and Skin Disease [RO1 AR063709]
- Japan Rheumatism Foundation
- Japan Society for the Promotion of Science
- Fundacion Bechara
- NIH [P30 AR070253]
- National Institute for Health Research/Wellcome Trust Clinical Research Facility at University Hospitals Birmingham NHS Foundation Trust
- Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE) [20298]
- Clinician Scientist Fellowship [18547]
- European Community's Collaborative project 'Euro-TEAM' [FP7-HEALTH-F2-2012-305549]
- [R01AR063759]
- [U01GM092691]
- [U19AI111224]
- Medical Research Council [1407712] Funding Source: researchfish
- MRC Arthritis UK Centre for MAR [Roche_Buckley] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0617-10128] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [16K09889] Funding Source: KAKEN
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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.
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