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. Watts, A. Helena Jonsson, Yunju Jeong, Humra Athar, Dylan Windell, Joyce B. Kang, Matthias Friedrich, Jason D. Turner, Saba Nayar, Benjamin A. Fisher, Karim Raza, Jennifer L. Marshall, Adam P. Croft, Tomoyoshi Tamura, Lynette M. Sholl, Marina Vivero, Iván O. Rosas, Simon Bowman, Mark Coles, Andreas P. Frei, Kara G. Lassen, Andrew Filer, Fiona Powrie, Christopher D. Buckley, Michael B. Brenner, Soumya Raychaudhuri
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: 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.