A revised airway epithelial hierarchy includes CFTR-expressing ionocytes

Daniel T. Montoro, Adam L. Haber, Moshe Biton, Vladimir Vinarsky, Brian Lin, Susan E. Birket, Feng Yuan, Sijia Chen, Hui Min Leung, Jorge Villoria, Noga Rogel, Grace Burgin, Alexander M. Tsankov, Avinash Waghray, Michal Slyper, Julia Waldman, Lan Nguyen, Danielle Dionne, Orit Rozenblatt-Rosen, Purushothama Rao Tata, Hongmei Mou, Manjunatha Shivaraju, Hermann Bihler, Martin Mense, Guillermo J. Tearney, Steven M. Rowe, John F. Engelhardt, Aviv Regev () and Jayaraj Rajagopal ()
Additional contact information
Daniel T. Montoro: Center for Regenerative Medicine, Massachusetts General Hospital
Adam L. Haber: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Moshe Biton: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Vladimir Vinarsky: Center for Regenerative Medicine, Massachusetts General Hospital
Brian Lin: Center for Regenerative Medicine, Massachusetts General Hospital
Susan E. Birket: University of Alabama at Birmingham
Feng Yuan: Carver College of Medicine, University of Iowa
Sijia Chen: Academic Medical Center/University of Amsterdam
Hui Min Leung: Massachusetts General Hospital
Jorge Villoria: Center for Regenerative Medicine, Massachusetts General Hospital
Noga Rogel: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Grace Burgin: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Alexander M. Tsankov: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Avinash Waghray: Center for Regenerative Medicine, Massachusetts General Hospital
Michal Slyper: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Julia Waldman: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Lan Nguyen: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Danielle Dionne: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Orit Rozenblatt-Rosen: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Purushothama Rao Tata: Duke University
Hongmei Mou: Massachusetts General Hospital
Manjunatha Shivaraju: Center for Regenerative Medicine, Massachusetts General Hospital
Hermann Bihler: Cystic Fibrosis Foundation
Martin Mense: Cystic Fibrosis Foundation
Guillermo J. Tearney: Massachusetts General Hospital
Steven M. Rowe: University of Alabama at Birmingham
John F. Engelhardt: Carver College of Medicine, University of Iowa
Aviv Regev: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Jayaraj Rajagopal: Center for Regenerative Medicine, Massachusetts General Hospital

Nature, 2018, vol. 560, issue 7718, 319-324

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0393-7

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