Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis

Tatsuya Tsukui, Kai-Hui Sun, Joseph B. Wetter, John R. Wilson-Kanamori, Lisa A. Hazelwood, Neil C. Henderson, Taylor S. Adams, Jonas C. Schupp, Sergio D. Poli, Ivan O. Rosas, Naftali Kaminski, Michael A. Matthay, Paul J. Wolters and Dean Sheppard ()
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Tatsuya Tsukui: University of California, San Francisco
Kai-Hui Sun: University of California, San Francisco
Joseph B. Wetter: Abbvie Inc
John R. Wilson-Kanamori: University of Edinburgh
Lisa A. Hazelwood: Abbvie Inc
Neil C. Henderson: University of Edinburgh
Taylor S. Adams: Yale School of Medicine
Jonas C. Schupp: Yale School of Medicine
Sergio D. Poli: Harvard Medical School
Ivan O. Rosas: Harvard Medical School
Naftali Kaminski: Yale School of Medicine
Michael A. Matthay: University of California, San Francisco
Paul J. Wolters: University of California, San Francisco
Dean Sheppard: University of California, San Francisco

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.

Date: 2020
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DOI: 10.1038/s41467-020-15647-5

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