1. Stem Cells and Regenerative Medicine
  2. Human Biology and Medicine
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Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids

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Cite this article as: eLife 2017;6:e26575 doi: 10.7554/eLife.26575

Abstract

The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants. We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids. Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated.

Article and author information

Author details

  1. Marko Z Nikolić

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Oriol Caritg

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Quitz Jeng

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Jo-Anne Johnson

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Dawei Sun

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Kate J Howell

    Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Jane L Brady

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Usua Laresgoiti

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. George Allen

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Richard Butler

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Matthias Zilbauer

    Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Adam Giangreco

    Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Emma L Rawlins

    Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    e.rawlins@gurdon.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7426-3792

Funding

Medical Research Council (G0900424)

  • Emma L Rawlins

Wellcome (PhD programme for clinicians fellowship)

  • Marko Z Nikolić

Addenbrooke's Charitable Trust, Cambridge University Hospitals (N/A)

  • Marko Z Nikolić

Ikerbasque, Basque Foundation for Science (N/A)

  • Usua Laresgoiti

Cancer Research UK (C6946/A14492)

  • Emma L Rawlins

Medical Research Council (MR/P009581/1)

  • Emma L Rawlins

Wellcome (Clinical PhD Fellowship)

  • Jo-Anne Johnson

Wellcome (92096)

  • Emma L Rawlins

Fundacio Universitaria Agusti Pedro i Pons (Short term fellowship)

  • Oriol Caritg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This research has been regulated under the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012 following ethical review by the University of Cambridge and University College London Animal Welfare and Ethical Review Body (AWERB). All experiments were thereafter conducted according to Home Office project licenses PPL 70/8012 (Emma Rawlins, University of Cambridge) and 70/7607 (Adam Giangreco, UCL).

Human subjects: Human embryonic and foetal lung tissue. Human embryonic and foetal lungs were obtained from terminations of pregnancy from Cambridge University Hospitals NHS Foundation Trust under permission from NHS Research Ethical Committee (96/085) and the Joint MRC/Wellcome Trust Human Developmental Biology Resource (London and Newcastle, grant 099175/Z/12/Z, www.hdbr.org). Informed consent and consent to publish was obtained.Human adult lung tissue. Fresh healthy adult lung tissue (background tissue from lobectomies for lung cancer) was obtained from Papworth Hospital NHS Foundation Trust (Research Tissue Bank Generic REC approval, Tissue Bank Project number T01939). Informed consent and consent to publish was obtained.

Reviewing Editor

  1. Marianne Bronner, California Institute of Technology, United States

Publication history

  1. Received: March 7, 2017
  2. Accepted: June 23, 2017
  3. Accepted Manuscript published: June 30, 2017 (version 1)
  4. Version of Record published: August 14, 2017 (version 2)

Copyright

© 2017, Nikolić et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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