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A revised airway epithelial hierarchy includes CFTR-expressing ionocytes

Author

Listed:
  • Daniel T. Montoro

    (Center for Regenerative Medicine, Massachusetts General Hospital
    Pulmonary and Critical Care Unit, Massachusetts General Hospital
    Harvard Stem Cell Institute
    Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Adam L. Haber

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Moshe Biton

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Vladimir Vinarsky

    (Center for Regenerative Medicine, Massachusetts General Hospital
    Pulmonary and Critical Care Unit, Massachusetts General Hospital
    Harvard Stem Cell Institute)

  • Brian Lin

    (Center for Regenerative Medicine, Massachusetts General Hospital
    Pulmonary and Critical Care Unit, Massachusetts General Hospital
    Harvard Stem Cell Institute)

  • Susan E. Birket

    (University of Alabama at Birmingham
    Gregory Fleming James Cystic Fibrosis Research Center)

  • Feng Yuan

    (Carver College of Medicine, University of Iowa)

  • Sijia Chen

    (Academic Medical Center/University of Amsterdam)

  • Hui Min Leung

    (Massachusetts General Hospital
    Massachusetts General Hospital)

  • Jorge Villoria

    (Center for Regenerative Medicine, Massachusetts General Hospital
    Pulmonary and Critical Care Unit, Massachusetts General Hospital
    Harvard Stem Cell Institute)

  • 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
    Pulmonary and Critical Care Unit, Massachusetts General Hospital
    Harvard Stem Cell Institute
    Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • 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
    Duke Cancer Institute, Duke University
    Duke University School of Medicine
    Regeneration Next, Duke University)

  • Hongmei Mou

    (Massachusetts General Hospital
    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital)

  • Manjunatha Shivaraju

    (Center for Regenerative Medicine, Massachusetts General Hospital
    Pulmonary and Critical Care Unit, Massachusetts General Hospital
    Harvard Stem Cell Institute)

  • Hermann Bihler

    (Cystic Fibrosis Foundation)

  • Martin Mense

    (Cystic Fibrosis Foundation)

  • Guillermo J. Tearney

    (Massachusetts General Hospital
    Massachusetts General Hospital)

  • Steven M. Rowe

    (University of Alabama at Birmingham
    Gregory Fleming James Cystic Fibrosis Research Center)

  • John F. Engelhardt

    (Carver College of Medicine, University of Iowa)

  • Aviv Regev

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology)

  • Jayaraj Rajagopal

    (Center for Regenerative Medicine, Massachusetts General Hospital
    Pulmonary and Critical Care Unit, Massachusetts General Hospital
    Harvard Stem Cell Institute
    Klarman Cell Observatory, Broad Institute of MIT and Harvard)

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.

Suggested Citation

  • 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. T, 2018. "A revised airway epithelial hierarchy includes CFTR-expressing ionocytes," Nature, Nature, vol. 560(7718), pages 319-324, August.
  • Handle: RePEc:nat:nature:v:560:y:2018:i:7718:d:10.1038_s41586-018-0393-7
    DOI: 10.1038/s41586-018-0393-7
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    Cited by:

    1. Yuanyuan Chen & Reka Toth & Sara Chocarro & Dieter Weichenhan & Joschka Hey & Pavlo Lutsik & Stefan Sawall & Georgios T. Stathopoulos & Christoph Plass & Rocio Sotillo, 2022. "Club cells employ regeneration mechanisms during lung tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yunpei Xu & Shaokai Wang & Qilong Feng & Jiazhi Xia & Yaohang Li & Hong-Dong Li & Jianxin Wang, 2024. "scCAD: Cluster decomposition-based anomaly detection for rare cell identification in single-cell expression data," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Tim Flerlage & Jeremy Chase Crawford & E. Kaitlynn Allen & Danielle Severns & Shaoyuan Tan & Sherri Surman & Granger Ridout & Tanya Novak & Adrienne Randolph & Alina N. West & Paul G. Thomas, 2023. "Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Yuan Guan & Annika Enejder & Meiyue Wang & Zhuoqing Fang & Lu Cui & Shih-Yu Chen & Jingxiao Wang & Yalun Tan & Manhong Wu & Xinyu Chen & Patrik K. Johansson & Issra Osman & Koshi Kunimoto & Pierre Rus, 2021. "A human multi-lineage hepatic organoid model for liver fibrosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Seunghan Han & Bomin Kim & Do Young Hyeon & Daeun Jeong & Jaechan Ryu & Jae-Sung Nam & Yoon Ha Choi & Bo-Ram Kim & Sang Chul Park & Youn Wook Chung & Sung Jae Shin & June-Yong Lee & Jong Kyoung Kim & , 2024. "Distinctive CD39+CD9+ lung interstitial macrophages suppress IL-23/Th17-mediated neutrophilic asthma by inhibiting NETosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Arthur S. Lee & Lauren J. Ayers & Michael Kosicki & Wai-Man Chan & Lydia N. Fozo & Brandon M. Pratt & Thomas E. Collins & Boxun Zhao & Matthew F. Rose & Alba Sanchis-Juan & Jack M. Fu & Isaac Wong & X, 2024. "A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    7. Leila R. Martins & Lina Sieverling & Michelle Michelhans & Chiara Schiller & Cihan Erkut & Thomas G. P. Grünewald & Sergio Triana & Stefan Fröhling & Lars Velten & Hanno Glimm & Claudia Scholl, 2024. "Single-cell division tracing and transcriptomics reveal cell types and differentiation paths in the regenerating lung," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Zhoufeng Wang & Zhe Li & Kun Zhou & Chengdi Wang & Lili Jiang & Li Zhang & Ying Yang & Wenxin Luo & Wenliang Qiao & Gang Wang & Yinyun Ni & Shuiping Dai & Tingting Guo & Guiyi Ji & Minjie Xu & Yiying , 2021. "Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    9. Andrew Berical & Rhianna E. Lee & Junjie Lu & Mary Lou Beermann & Jake A. Le Suer & Aditya Mithal & Dylan Thomas & Nicole Ranallo & Megan Peasley & Alex Stuffer & Katherine Bukis & Rebecca Seymour & J, 2022. "A multimodal iPSC platform for cystic fibrosis drug testing," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Katarina Kulhankova & Soumba Traore & Xue Cheng & Hadrien Benk-Fortin & Stéphanie Hallée & Mario Harvey & Joannie Roberge & Frédéric Couture & Sajeev Kohli & Thomas J. Gross & David K. Meyerholz & Gar, 2023. "Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Quinn T. Easter & Bruno Fernandes Matuck & Germán Beldorati Stark & Catherine L. Worth & Alexander V. Predeus & Brayon Fremin & Khoa Huynh & Vaishnavi Ranganathan & Zhi Ren & Diana Pereira & Brittany , 2024. "Single-cell and spatially resolved interactomics of tooth-associated keratinocytes in periodontitis," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    12. Taghreed Hirz & Shenglin Mei & Hirak Sarkar & Youmna Kfoury & Shulin Wu & Bronte M. Verhoeven & Alexander O. Subtelny & Dimitar V. Zlatev & Matthew W. Wszolek & Keyan Salari & Evan Murray & Fei Chen &, 2023. "Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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