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

TLDR

Collagen‑producing cells maintain lung architecture and drive pathological scarring in pulmonary fibrosis. The study uses single‑cell RNA‑sequencing to identify all collagen‑producing cells in normal and fibrotic lungs. The authors performed single‑cell RNA‑sequencing of mouse and human lungs, purified collagen‑producing subpopulations, and characterized disease‑relevant phenotypes of CTHRC1‑expressing fibroblasts through in vitro assays and adoptive transfer experiments. The atlas identifies multiple collagen‑producing subpopulations with distinct anatomical localizations, including a CTHRC1‑expressing fibroblast subset that is enriched in fibrotic lungs, concentrated within fibroblastic foci, and exhibits disease‑relevant phenotypes, offering a roadmap for studying their roles in homeostasis and fibrosis.

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.