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Nature. 2018 Aug;560(7718):319-324. doi: 10.1038/s41586-018-0393-7. Epub 2018 Aug 1.

A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.

Author information

1
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
2
Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA, USA.
3
Harvard Stem Cell Institute, Cambridge, MA, USA.
4
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
6
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
7
Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, AL, USA.
8
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
9
Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
10
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
11
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA.
12
Department of Cell Biology, Duke University, Durham, NC, USA.
13
Duke Cancer Institute, Duke University, Durham, NC, USA.
14
Division of Pulmonary Critical Care, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
15
Regeneration Next, Duke University, Durham, NC, USA.
16
Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA.
17
Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
18
CFFT Lab, Cystic Fibrosis Foundation, Lexington, MA, USA.
19
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.
20
Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org.
21
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. jrajagopal@mgh.harvard.edu.
22
Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA, USA. jrajagopal@mgh.harvard.edu.
23
Harvard Stem Cell Institute, Cambridge, MA, USA. jrajagopal@mgh.harvard.edu.
24
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. jrajagopal@mgh.harvard.edu.

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.

PMID:
30069044
DOI:
10.1038/s41586-018-0393-7

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