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Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis
Yan Xu, … , Barry R. Stripp, Jeffrey A. Whitsett
Yan Xu, … , Barry R. Stripp, Jeffrey A. Whitsett
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e90558. https://doi.org/10.1172/jci.insight.90558.
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Research Article Inflammation

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing (scRNA-seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 (AT1), AT2, and conducting airway selective markers, demonstrating “indeterminate” states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-β, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease.

Authors

Yan Xu, Takako Mizuno, Anusha Sridharan, Yina Du, Minzhe Guo, Jie Tang, Kathryn A. Wikenheiser-Brokamp, Anne-Karina T. Perl, Vincent A. Funari, Jason J. Gokey, Barry R. Stripp, Jeffrey A. Whitsett

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Figure 1

Heatmap, principal component analysis, and predicted function in sorted normal and IPF epithelial cells.

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Heatmap, principal component analysis, and predicted function in sorted ...
EPCAM+ (CD326+) and HTII-280+ epithelial cells from control and IPF donors were isolated from peripheral lung tissue by FACS and subjected to RNA sequencing (RNA-seq). (A) Principal component analysis (PCA) RNA-seq data from IPF and control donors (n = 3 per group) shows the primary separation of samples by disease status. (B) Heatmap represents 2D hierarchical clustering of genes and samples and shows differentially expressed genes in IPF versus control samples. (C) Functional enrichment of predicted biological processes and genes induced in IPF is shown. (D) Functional enrichment of predicted biological processes and genes suppressed in IPF is shown. x axis represents the –log10 transformed enrichment P value

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