Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis.
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IF: 30.528
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Cited by: 700
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Abstract

Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.

Keywords

RNAscope
Spatial Transcriptomics
Seurat
RNA sequencing
alveolar macrophages
alveolar type II cells
pulmonary fibrosis

MeSH terms

Animals
Cells, Cultured
Disease Models, Animal
Epithelial Cells
Female
Humans
Idiopathic Pulmonary Fibrosis
Male
Sequence Analysis, RNA
Stem Cells
Transcriptome

Authors

Reyfman, Paul A
Walter, James M
Joshi, Nikita
Anekalla, Kishore R
McQuattie-Pimentel, Alexandra C
Chiu, Stephen
Fernandez, Ramiro
Akbarpour, Mahzad
Chen, Ching-I
Ren, Ziyou
Verma, Rohan
Abdala-Valencia, Hiam
Nam, Kiwon
Chi, Monica
Han, SeungHye
Gonzalez-Gonzalez, Francisco J
Soberanes, Saul
Watanabe, Satoshi
Williams, Kinola J N
Flozak, Annette S
Nicholson, Trevor T
Morgan, Vince K
Winter, Deborah R
Hinchcliff, Monique
Hrusch, Cara L
Guzy, Robert D
Bonham, Catherine A
Sperling, Anne I
Bag, Remzi
Hamanaka, Robert B
Mutlu, Gökhan M
Yeldandi, Anjana V
Marshall, Stacy A
Shilatifard, Ali
Amaral, Luis A N
Perlman, Harris
Sznajder, Jacob I
Argento, A Christine
Gillespie, Colin T
Dematte, Jane
Jain, Manu
Singer, Benjamin D
Ridge, Karen M
Lam, Anna P
Bharat, Ankit
Bhorade, Sangeeta M
Gottardi, Cara J
Budinger, G R Scott
Misharin, Alexander V

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