Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

被引：445

作者：

Mizoguchi, Fumitaka ^{[1
,17
]}

Slowikowski, Kamil ^{[2
,3
,4
,5
]}

Wei, Kevin ^{[1
]}

Marshall, Jennifer L. ^{[6
]}

Rao, Deepak A. ^{[1
]}

Chang, Sook Kyung ^{[1
,18
]}

Nguyen, Hung N. ^{[1
]}

Noss, Erika H. ^{[1
,19
]}

Turner, Jason D. ^{[6
]}

Earp, Brandon E. ^{[7
]}

Blazar, Philip E. ^{[7
]}

Wright, John ^{[7
]}

Simmons, Barry P. ^{[7
]}

Donlin, Laura T. ^{[8
,9
,10
]}

Kalliolias, George D. ^{[8
,9
]}

Goodman, Susan M. ^{[8
,9
,10
]}

Bykerk, Vivian P. ^{[8
,9
,10
]}

Ivashkiv, Lionel B. ^{[8
,9
,10
]}

Lederer, James A. ^{[11
,12
]}

Hacohen, Nir ^{[3
,13
,14
]}

Nigrovic, Peter A. ^{[1
,15
]}

Filer, Andrew ^{[6
]}

Buckley, Christopher D. ^{[6
]}

Raychaudhuri, Soumya ^{[1
,2
,3
,5
,16
,17
]}

Brenner, Michael B. ^{[1
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02446 USA

[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[4] Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA

[5] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[6] Univ Birmingham, Queen Elizabeth Hosp, Rheumatol Res Grp, IIA, Birmingham B15 2WB, W Midlands, England

[7] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA

[8] Hosp Special Surg, Arthrit & Tissue Degenerat Program, New York, NY 10021 USA

[9] Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY 10021 USA

[10] Weill Cornell Grad Sch Med Sci, New York, NY 10021 USA

[11] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA

[12] Harvard Med Sch, Boston, MA 02115 USA

[13] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02114 USA

[14] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[15] Boston Childrens Hosp, Harvard Med Sch, Dept Med, Div Immunol, Boston, MA 02115 USA

[16] Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Ctr Genet & Genom, Manchester M13 9PT, Lancs, England

[17] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Rheumatol, Tokyo 1138519, Japan

[18] JW Creagene Corp, Seongnam Si 13202, South Korea

[19] Univ Washington, Div Rheumatol, Seattle, WA 98109 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国惠康基金; 日本学术振兴会;

关键词：

SYNOVIAL FIBROBLASTS; RNA-SEQ; MATRIX-METALLOPROTEINASE; IMMUNOLOGICAL HALLMARKS; CADHERIN-11; CELLS; SYNOVIOCYTES; INFLAMMATION; INVASION; RANKL;

D O I：

10.1038/s41467-018-02892-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：11

共 45 条

[1]

[Anonymous], 2014, CURR PROTOC MOL BIOL, DOI DOI 10.1002/0471142727.MB0422S107

[2]

Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes [J].