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, Dean Sheppard

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1920
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 21 Apr 2020

Keywords

  • Animals
  • Cell Separation
  • Collagen/chemistry
  • Extracellular Matrix Proteins/metabolism
  • Female
  • Fibroblasts/metabolism
  • Flow Cytometry
  • Green Fluorescent Proteins/metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Idiopathic Pulmonary Fibrosis/pathology
  • Lung/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Pulmonary Fibrosis/metabolism
  • Respiration Disorders/metabolism
  • Single-Cell Analysis

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