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; Sam 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; Marino 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

Ilya Korsunsky, Kevin Wei, Mathilde Pohin, Edy Y. Kim, Francesca Barone, Triin Major, Emily Taylor, Rahul Ravindran, Sam 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 RazaJennifer L. Marshall, Adam P. Croft, Tomoyoshi Tamura, Lynette M. Sholl, Marino 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	481-518
Number of pages	53
Journal	Med
Volume	3
Issue number	7
Early online date	31 May 2022
DOIs	https://doi.org/10.1016/j.medj.2022.05.002
Publication status	Published - 8 Jul 2022

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Korsunsky, I., Wei, K., Pohin, M., Kim, E. Y., Barone, F., Major, T., Taylor, E., Ravindran, R., Kemble, S., Watts, G. F. M., Jonsson, A. H., Jeong, Y., Athar, H., Windell, D., Kang, J. B., Friedrich, M., Turner, J., Nayar, S., Fisher, B. A., ... Raychaudhuri, S. (2022). Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med, 3(7), 481-518. https://doi.org/10.1016/j.medj.2022.05.002

@article{7648bec827204cbaa44eddc3d331357f,

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

abstract = "BackgroundPro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sj{\"o}gren{\textquoteright}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.MethodsWe 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.FindingsTwo 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.ConclusionsThis 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.FundingGrant from F. Hoffmann-La Roche (Roche) AG.",

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

year = "2022",

month = jul,

day = "8",

doi = "10.1016/j.medj.2022.05.002",

language = "English",

volume = "3",

pages = "481--518",

journal = "Med",

issn = "2666-6359",

publisher = "Cell Press",

number = "7",

}

Korsunsky, I, Wei, K, Pohin, M, Kim, EY, Barone, F, Major, T, Taylor, E, Ravindran, R, Kemble, S, Watts, GFM, Jonsson, AH, Jeong, Y, Athar, H, Windell, D, Kang, JB, Friedrich, M, Turner, J , Nayar, S , Fisher, BA , Raza, K , Marshall, JL , Croft, AP, Tamura, T, Sholl, LM, Vivero, M, Rosas, IO, Bowman, SJ, Coles, M, Frei, AP, Lassen, K, Filer, A, Powrie, F, Buckley, CD, Brenner, MB & Raychaudhuri, S 2022, 'Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases', Med, vol. 3, no. 7, pp. 481-518. https://doi.org/10.1016/j.medj.2022.05.002

TY - JOUR

T1 - Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

AU - Korsunsky, Ilya

AU - Wei, Kevin

AU - Pohin, Mathilde

AU - Kim, Edy Y.

AU - Barone, Francesca

AU - Major, Triin

AU - Taylor, Emily

AU - Ravindran, Rahul

AU - Kemble, Sam

AU - Watts, Gerald F. M.

AU - Jonsson, A. Helena

AU - Jeong, Yunju

AU - Athar, Humra

AU - Windell, Dylan

AU - Kang, Joyce B.

AU - Friedrich, Matthias

AU - Turner, Jason

AU - Nayar, Saba

AU - Fisher, Benjamin A.

AU - Raza, Karim

AU - Marshall, Jennifer L.

AU - Croft, Adam P.

AU - Tamura, Tomoyoshi

AU - Sholl, Lynette M.

AU - Vivero, Marino

AU - Rosas, Ivan O.

AU - Bowman, Simon J.

AU - Coles, Mark

AU - Frei, Andreas P.

AU - Lassen, Kara

AU - Filer, Andrew

AU - Powrie, Fiona

AU - Buckley, Christopher D.

AU - Brenner, Michael B.

AU - Raychaudhuri, Soumya

PY - 2022/7/8

Y1 - 2022/7/8

N2 - BackgroundPro-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.MethodsWe 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.FindingsTwo 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.ConclusionsThis 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.FundingGrant from F. Hoffmann-La Roche (Roche) AG.

AB - BackgroundPro-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.MethodsWe 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.FindingsTwo 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.ConclusionsThis 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.FundingGrant from F. Hoffmann-La Roche (Roche) AG.

UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85132864748&partnerID=MN8TOARS

U2 - 10.1016/j.medj.2022.05.002

DO - 10.1016/j.medj.2022.05.002

M3 - Article

SN - 2666-6359

VL - 3

SP - 481

EP - 518

JO - Med

JF - Med

IS - 7

ER -

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

Abstract

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