A revised airway epithelial hierarchy includes CFTR-expressing ionocytes
Open accessAbstract
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.
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- Authors
- Montoro, D. T., Haber, A. L., Biton, M., Vinarsky, V., Lin, B., Birket, S. E., Yuan, F., Chen, S., Leung, H. M., Villoria, J., Rogel, N., Burgin, G., Tsankov, A. M., Waghray, A., Slyper, M., Waldman, J., Nguyen, L., Dionne, D., Rozenblatt-Rosen, O., Tata, P. R., Mou, H., Shivaraju, M., Bihler, H., Mense, M., Tearney, G. J., Rowe, S. M., Engelhardt, J. F., Regev, A., & Rajagopal, J.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- University of Alabama at Birmingham (US)
- University of Iowa (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- Massachusetts General Hospital (US)
- Duke University (US)
- Cystic Fibrosis Foundation (US)
- ORCID
- Montoro, Daniel T.
- Haber, Adam L.
- Biton, Moshe
- Lin, Brian
- Birket, Susan E.
- Yuan, Feng
- Chen, Sijia
- Leung, Hui Min
- Tsankov, Alexander M.
- Waghray, Avinash
- Slyper, Michal
- Waldman, Julia
- Dionne, Danielle
- Tata, Purushothama Rao
- Mou, Hongmei
- Shivaraju, Manjunatha
- Bihler, Hermann
- Mense, Martin
- Tearney, Guillermo J.
- Rowe, Steven M.
- Engelhardt, John F.
- Regev, Aviv
- Rajagopal, Jayaraj
- Venue
- Nature
- Published
- 2018-08-01
- Volume
- 560
- Issue
- 7718
- Pages
- 319-324
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6295155
- OpenAlex
- W2887886950
- Cited by
- 1,206
- References
- 77
- Citations by year
- 2026: 85 · 2025: 140 · 2024: 163 · 2023: 132 · 2022: 182 · 2021: 183 · 2020: 175 · 2019: 117 · 2018: 28
- FWCI
- 44.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- New York Stem Cell Foundation
- Broad Institute
- Manton Foundation
- National Institutes of Health (NIH P30 DK072482, HL051670, DK072482, DK047967)
- Harvard Stem Cell Institute
- Klarman Cell Observatory, Broad Institute
- National Heart, Lung, and Blood Institute (R35HL135816, P01HL051670, HL-051670, K99HL127181, HL135816, R24HL123482, R00HL127181, F31HL136128, HL123482, DK072482, K08HL131867)
- National Institute on Drug Abuse (R01DA047967)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK047967, P30DK072482, P30DK043351, P30DK054759)
- National Institute of Environmental Health Sciences (P30ES005605)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- airway epithelium, CFTR, FOXI1, tracheal epithelium, Clara cells, hillocks, tuft cells, goblet cells, neuroendocrine cells, basal progenitor cells, cell turnover, cystic fibrosis, asthma, airway mucus, lineage tracing
- MeSH terms
- Animals, Asthma, Cell Differentiation, Cystic Fibrosis, Epithelial Cells, Female, Gene Expression Regulation, Humans, Lung, Male, Trachea, Sequence Analysis, RNA, Cystic Fibrosis Transmembrane Conductance Regulator, Cell Lineage, Goblet Cells, Gene Expression Profiling, Mice, Forkhead Transcription Factors, Single-Cell Analysis
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