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

Korsunsky, I.; Wei, K.; Pohin, M.; Kim, E. Y.; Barone, F.; Kang, J. B.; Friedrich, M.; Turner, J.; Nayar, S.; Fisher, B. A.; Raza, K.; Marshall, J. L.; Croft, A. P.; Sholl, L. M.; Vivero, M.; Rosas, I. O.; Bowman, S. J.; Coles, M.; Frei, A. P.; Lassen, K.; Filer, A.; Powrie, F.; Buckley, C. D.; Brenner, M. B.; Raychaudhuri, S.

doi:10.1101/2021.01.11.426253

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bioRxiv · 10.1101/2021.01.11.426253

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

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Abstract

Pro-inflammatory fibroblasts are critical to pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjogrens 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 the understanding of which pathways are shared by multiple diseases. To investigate, we profiled patient-derived fibroblasts from inflamed and non-inflamed synovium, intestine, lung, and salivary glands with single-cell RNA-sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts were expanded in all inflamed tissues and additionally mapped to dermal analogues in a public atopic dermatitis atlas. We further confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. This work represents the first cross-tissue, single-cell fibroblast atlas revealing shared pathogenic activation states across four chronic inflammatory diseases.

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Korsunsky, I., Wei, K., Pohin, M., Kim, E. Y., Barone, F., Kang, J. B., Friedrich, M., Turner, J., Nayar, S., Fisher, B. A., Raza, K., Marshall, J. L., Croft, A. P., Sholl, L. M., Vivero, M., Rosas, I. O., Bowman, S. J., Coles, M., Frei, A. P., Lassen, K., Filer, A., Powrie, F., Buckley, C. D., Brenner, M. B., Raychaudhuri, S.. 2021-01-12. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. https://doi.org/10.1101/2021.01.11.426253

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