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; Jayaraj Rajagopal

doi:10.1038/s41586-018-0393-7

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A revised airway epithelial hierarchy includes CFTR-expressing ionocytes

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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, …

Nature (London), Vol.560(7718), pp.319-324

08/2018

DOI: 10.1038/s41586-018-0393-7

PMCID: PMC6295155

PMID: 30069044

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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.

Details

Title: Subtitle: A revised airway epithelial hierarchy includes CFTR-expressing ionocytes
Creators: Daniel T Montoro - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Adam L Haber - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Moshe Biton - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
Vladimir Vinarsky - Harvard Stem Cell Institute, Cambridge, MA, USA
Brian Lin - Harvard Stem Cell Institute, Cambridge, MA, USA
Susan E Birket - Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, AL, USA
Feng Yuan - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Sijia Chen - Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
Hui Min Leung - Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
Jorge Villoria - Harvard Stem Cell Institute, Cambridge, MA, USA
Noga Rogel - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Grace Burgin - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Alexander M Tsankov - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Avinash Waghray - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Michal Slyper - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Julia Waldman - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Lan Nguyen - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Danielle Dionne - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Orit Rozenblatt-Rosen - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Purushothama Rao Tata - Regeneration Next, Duke University, Durham, NC, USA
Hongmei Mou - Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA
Manjunatha Shivaraju - Harvard Stem Cell Institute, Cambridge, MA, USA
Hermann Bihler - CFFT Lab, Cystic Fibrosis Foundation, Lexington, MA, USA
Martin Mense - CFFT Lab, Cystic Fibrosis Foundation, Lexington, MA, USA
Guillermo J Tearney - Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
Steven M Rowe - Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, AL, USA
John F Engelhardt - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Aviv Regev - Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org
Jayaraj Rajagopal - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. jrajagopal@mgh.harvard.edu
Resource Type: Journal article
Publication Details: Nature (London), Vol.560(7718), pp.319-324
Publisher: England
DOI: 10.1038/s41586-018-0393-7
PMID: 30069044
PMCID: PMC6295155
ISSN: 0028-0836
eISSN: 1476-4687
Grant note: R35 HL135816 / NHLBI NIH HHS P30 DK072482 / NIDDK NIH HHS R00 HL127181 / NHLBI NIH HHS F31 HL136128 / NHLBI NIH HHS K99 HL127181 / NHLBI NIH HHS
Language: English
Date published: 08/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025312202771

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