Letter | Published:

Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor

Nature volume 555, pages 251255 (08 March 2018) | Download Citation

Abstract

Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration1; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration2,3. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (T32-HL007586 to W.J.Z; T32-HL007915, K12-HD043245 to D.B.F., T32-HL007843 to J.A.Z. and HL110942, HL087825, HL132999, HL129478, HL134745 to E.E.M.). We thank the Flow Cytometry Core Laboratory of Children’s Hospital of Philadelphia and the CVI Histology Core, Next Generation Sequencing Core and CDB Microscopy Core at the University of Pennsylvania for technical assistance.

Author information

Author notes

    • William J. Zacharias
    •  & David B. Frank

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • William J. Zacharias
    • , Jarod A. Zepp
    • , Michael P. Morley
    • , Farrah A. Alkhaleel
    • , Jun Kong
    • , Su Zhou
    •  & Edward E. Morrisey
  2. Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • William J. Zacharias
    • , David B. Frank
    • , Jarod A. Zepp
    • , Michael P. Morley
    • , Farrah A. Alkhaleel
    • , Jun Kong
    •  & Edward E. Morrisey
  3. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA

    • David B. Frank
  4. Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • David B. Frank
    • , Michael P. Morley
    • , Su Zhou
    •  & Edward E. Morrisey
  5. Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Edward Cantu
  6. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Edward E. Morrisey
  7. Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Edward E. Morrisey

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Contributions

W.J.Z., D.B.F., J.A.Z., F.A.A., S.Z. and J.K. performed the experiments. W.J.Z., D.B.F., J.A.Z., M.P.M. and E.E.M. analysed the data. E.C. provided access to human samples and assisted W.J.Z. with all human experiments. E.E.M. supervised the project. W.J.Z. wrote the first draft of the manuscript. All authors contributed to the writing of the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Edward E. Morrisey.

Reviewer Information Nature thanks C. Dean and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Genes differentially expressed in mouse AEPs compared to mouse AT2 cells

  2. 2.

    Supplementary Table 2

    Genes differentially expressed in human AEPs compared to other human AT2 cells.

About this article

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DOI

https://doi.org/10.1038/nature25786

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