TY - JOUR T1 - Single Cell Transcriptomics and Flow Cytometry Reveal Disease-associated Fibroblast Subsets in Rheumatoid Arthritis JF - bioRxiv DO - 10.1101/126193 SP - 126193 AU - Fumitaka Mizoguchi AU - Kamil Slowikowski AU - Jennifer L Marshall AU - Kevin Wei AU - Deepak A Rao AU - Sook Kyung Chang AU - Hung N Nguyen AU - Erika H Noss AU - Jason D Turner AU - Brandon E Earp AU - Philip E Blazar AU - John Wright AU - Barry P Simmons AU - Laura T Donlin AU - George D Kalliolias AU - Susan M Goodman AU - Vivian P Bykerk AU - Lionel B Ivashkiv AU - James A Lederer AU - Nir Hacohen AU - Peter A Nigrovic AU - Andrew Filer AU - Christopher D Buckley AU - Soumya Raychaudhuri AU - Michael B Brenner Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/05/26/126193.abstract N2 - Fibroblasts mediate normal tissue matrix remodeling, but they can cause fibrosis or tissue destruction following chronic inflammation. In rheumatoid arthritis (RA), synovial fibroblasts expand, degrade cartilage, and drive joint inflammation. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to disease pathology. Here, we used an integrative strategy, including bulk transcriptomics on targeted subpopulations and unbiased single-cell transcriptomics, to analyze fibroblasts from synovial tissues. We identify 7 phenotypic fibroblast subsets with distinct surface protein phenotypes, and these collapsed into 3 subsets based on transcriptomics data. One subset expressing PDPN, THY1, but lacking CD34 was 3-fold expanded in RA relative to osteoarthritis (P=0.007); most of these cells expressed CDH11. The subsets were found to differ in expression of cytokines and matrix metalloproteinases, localization in synovial microanatomy, and in response to TNF. Our approach provides a template to identify pathogenic stromal cellular subsets in complex diseases. ER -