Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

Ilya Korsunsky; Kevin Wei; Mathilde Pohin; Edy Y Kim; Francesca Barone; Triin Major; Emily Taylor; Rahul Ravindran; Samuel Kemble; Gerald F M Watts; A Helena Jonsson; Yunju Jeong; Humra Athar; Dylan Windell; Joyce B Kang; Matthias Friedrich; Jason Turner; Saba Nayar; Benjamin A Fisher; Karim Raza; Jennifer L Marshall; Adam P Croft; Tomoyoshi Tamura; Lynette M Sholl; Marina Vivero; Ivan O Rosas; Simon J Bowman; Mark Coles; Andreas P Frei; Kara Lassen; Andrew Filer; Fiona Powrie; Christopher D Buckley; Michael B Brenner; Soumya Raychaudhuri

doi:10.1016/j.medj.2022.05.002

Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

Med. 2022 Jul 8;3(7):481-518.e14. doi: 10.1016/j.medj.2022.05.002. Epub 2022 May 31.

Authors

Ilya Korsunsky¹, Kevin Wei², Mathilde Pohin³, Edy Y Kim⁴, Francesca Barone⁵, Triin Major⁶, Emily Taylor⁶, Rahul Ravindran³, Samuel Kemble⁵, Gerald F M Watts², A Helena Jonsson², Yunju Jeong⁴, Humra Athar⁷, Dylan Windell³, Joyce B Kang¹, Matthias Friedrich³, Jason Turner⁶, Saba Nayar⁸, Benjamin A Fisher⁹, Karim Raza⁹, Jennifer L Marshall⁵, Adam P Croft⁵, Tomoyoshi Tamura⁴, Lynette M Sholl¹⁰, Marina Vivero¹⁰, Ivan O Rosas¹¹, Simon J Bowman⁹, Mark Coles³, Andreas P Frei¹², Kara Lassen¹², Andrew Filer⁸, Fiona Powrie¹³, Christopher D Buckley¹⁴, Michael B Brenner¹⁵, Soumya Raychaudhuri¹⁶

Affiliations

¹ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
² Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, UK.
⁴ Harvard Medical School, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵ Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WD, UK.
⁶ Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WD, UK; Birmingham Tissue Analytics, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, UK.
⁷ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁸ Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WD, UK; Birmingham Tissue Analytics, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK.
⁹ Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WD, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK.
¹⁰ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹¹ Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Dallas, TX 75246, USA.
¹² Roche Pharma Research and Early Development, Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center Basel, Basel 4070, Switzerland.
¹³ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, UK. Electronic address: [email protected].
¹⁴ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, UK; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WD, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK. Electronic address: [email protected].
¹⁵ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
¹⁶ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester M14 9PR UK. Electronic address: [email protected].

Abstract

Background: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.

Methods: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.

Findings: Two shared clusters, CXCL10⁺CCL19⁺ immune-interacting and SPARC⁺COL3A1⁺ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.

Conclusions: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.

Funding: Grant from F. Hoffmann-La Roche (Roche) AG.

Keywords: Foundational research; Sjögren's syndrome; atlas; fibroblasts; inflammation; integration; interstitial lung disease; rheumatoid arthritis; scRNA-seq; stromal; ulcerative colitis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis, Rheumatoid* / genetics
Fibroblasts / metabolism
Phenotype
Stromal Cells / metabolism
Synovial Membrane*

Abstract

Publication types

MeSH terms

Grants and funding