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.
Highlights
Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis
We identify a unique population of Cthrc1+ fibroblasts, which are mostly found in fibrotic lungs in both mice and humans and expresses the highest levels of type 1 collagen and other extracellular matrix (ECM) genes
Our results confirm that smooth muscle cells and pericytes express low levels of collagen in both mice and humans, but that there are unique populations of cells that express higher levels of collagen and reside in distinct anatomic locations—the walls of conducting airways, surrounding the bronchovascular bundles, and embedded within the gasexchanging alveolar region
Summary
Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. We use gene expression signatures to classify fibroblast subpopulations based on their anatomical localizations, and developed fluorescenceactivated cell sorting (FACS) strategies to purify those populations Through this approach, we identify molecularly distinct populations of fibroblasts that populate distinct anatomic locations, in the walls of conducting airways (peribronchial), surrounding bronchovascular bundles (adventitial) and embedded within the alveolar regions of the lung (alveolar). We identify a unique population of Cthrc[1] (collagen triple helix repeat containing 1)+ fibroblasts, which are mostly found in fibrotic lungs in both mice and humans and expresses the highest levels of type 1 collagen and other ECM genes. Purified Cthrc1+ fibroblasts are more migratory than other subsets of collagen-producing cells and demonstrate an enhanced capacity to colonize the lungs of bleomycin-treated mice These findings identify the distinct gene and cell surface protein expression patterns that characterize fibroblast subsets with distinct anatomic localizations. The Cthrc1+ subset we describe is likely to play an important role in the development of pulmonary fibrosis in mice and humans
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