Journal Article

A revised airway epithelial hierarchy includes CFTR-expressing ionocytes

Montoro, Daniel T., Rajagopal, Jayaraj, Biton, Moshe, Slyper, Michal, Lin, Brian, Tata, Purushothama Rao, Chen, Sijia, Birket, Susan E., Tearney, Guillermo J., Vinarsky, Vladimir, Burgin, Grace, Dionne, Danielle, Mou, Hongmei, Villoria, Jorge, Leung, Hui Min, Rogel, Noga, Tsankov, Alexander M., Bihler, Hermann, Shivaraju, Manjunatha, Haber, Adam L., Nguyen, Lan, Regev, Aviv, Rozenblatt-Rosen, Orit, Engelhardt, John F., Waghray, Avinash, Mense, Martin, Waldman, Julia, Yuan, Feng, Rowe, Steven M.

2018

Overview

The airways of the lung are the primary sites of disease in asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal epithelium by single-cell RNA-sequencing (scRNA-seq) and in vivo lineage tracing. We identify a rare cell type, the Foxi1 + pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that we term ‘hillocks’; and disease-relevant subsets of tuft and goblet cells. We developed ‘pulse-seq’, combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the cystic fibrosis transmembrane conductance regulator in both mouse ( Cftr ) and human ( CFTR ). Knockout of Foxi1 in mouse ionocytes causes loss of Cftr expression and disrupts airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease. Single-cell RNA sequencing analysis identifies cell types and lineages in airway epithelium, including the pulmonary ionocyte, a new cell type predominantly expressing the cystic fibrosis gene CFTR .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 13/106 / 13/31 / 13/51 / 14 / 14/19 / 14/32 / 38 / 38/35 / 38/77 / 45/91 / 631/114/2114 / 631/136/532/1360 / 631/136/532/489 / 631/337/2019 / 96 / Analysis / Animals / Asthma / Asthma - genetics / Bioinformatics / Cell Differentiation - genetics / Cell Lineage - genetics / Cell regulation / Cells (biology) / Cystic fibrosis / Cystic Fibrosis - genetics / Cystic Fibrosis Transmembrane Conductance Regulator - genetics / Disease / Epithelial cells / Epithelial Cells - cytology / Epithelial Cells - metabolism / Epithelium / Female / Fibrosis / Forkhead Transcription Factors - deficiency / Forkhead Transcription Factors - genetics / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Gene sequencing / Genes / Genetic aspects / Genetic research / Genomes / Goblet cells / Goblet Cells - cytology / Goblet Cells - metabolism / Humanities and Social Sciences / Humans / Lung / Lung - cytology / Lungs / Male / Mice / Mucus / multidisciplinary / Phenotypes / Physiological aspects / Progenitor cells / Respiratory tract / Ribonucleic acid / RNA / RNA sequencing / Science / Science (multidisciplinary) / Sequence Analysis, RNA / Single-Cell Analysis / Stem cells / Trachea - cytology / Transcription factors