Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

Fumitaka Mizoguchi,Michael B Brenner,Jason D Turner,Hung N Nguyen,Vivian P Bykerk,Nir Hacohen,Soumya Raychaudhuri,Deepak A Rao,John Wright,Christopher D Buckley,Andrew Filer,Susan M Goodman,Kamil Slowikowski,Kevin Wei,Song Ho Chang ,George D Kalliolias,James A Lederer,Jennifer L Marshall,Peter A Nigrović ,Barry P Simmons,Erika H Noss,Brandon E Earp,Laura T Donlin,Philip E Blazar,Lionel B Ivashkiv

doi:10.1038/s41467-018-02892-y

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.

Highlights

Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage
We acknowledge that the presence or absence of swelling is not a robust parameter to reflect joint inflammation, we found that the swollen joints had fewer CD34–THY1– (P = 0.02), more CD34–THY1+ (P = 0.09), and more CD34+ fibroblasts (P = 0.01 (Wilcoxon's rank-sum test))
This study identifies subsets of fibroblasts in fresh human synovium, including a distinct subset of PDPN+CD34–THY1+ fibroblasts that is expanded in rheumatoid arthritis (RA) and may be pathogenic

Summary

Introduction

Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. 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. Fibroblasts are important mediators of end-organ pathology and inflammation in chronic inflammatory and fibrotic diseases. Global transcriptomic analysis has revealed distinct activation states and cellular subsets of immune cells[7]. These approaches offer an opportunity to examine how stromal cells mediate various types of local tissue pathology. Synovial fibroblasts secrete inflammatory cytokines and chemokines, invade and degrade cartilage, and stimulate osteoclasts that cause bone erosion[2,4]

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