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Alveolar progenitor and stem cells in lung development, renewal and cancer

Author

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  • Tushar J. Desai

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Douglas G. Brownfield

    (Stanford University School of Medicine)

  • Mark A. Krasnow

    (Stanford University School of Medicine)

Abstract

Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.

Suggested Citation

  • Tushar J. Desai & Douglas G. Brownfield & Mark A. Krasnow, 2014. "Alveolar progenitor and stem cells in lung development, renewal and cancer," Nature, Nature, vol. 507(7491), pages 190-194, March.
  • Handle: RePEc:nat:nature:v:507:y:2014:i:7491:d:10.1038_nature12930
    DOI: 10.1038/nature12930
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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. Maik Pietzner & Robert Lorenz Chua & Eleanor Wheeler & Katharina Jechow & Julian D. S. Willett & Helena Radbruch & Saskia Trump & Bettina Heidecker & Hugo Zeberg & Frank L. Heppner & Roland Eils & Mar, 2022. "ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. 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.
    4. Kuei-Pin Chung & Chih-Ning Cheng & Yi-Jung Chen & Chia-Lang Hsu & Yen-Lin Huang & Min-Shu Hsieh & Han-Chun Kuo & Ya-Ting Lin & Yi-Hsiu Juan & Kiichi Nakahira & Yen-Fu Chen & Wei-Lun Liu & Sheng-Yuan R, 2024. "Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    5. Dalia Hassan & Jichao Chen, 2024. "CEBPA restricts alveolar type 2 cell plasticity during development and injury-repair," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Douglas G. Brownfield & Alex Diaz Arce & Elisa Ghelfi & Astrid Gillich & Tushar J. Desai & Mark A. Krasnow, 2022. "Alveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Ning Yang & Joseph M. Luna & Peihong Dai & Yi Wang & Charles M. Rice & Liang Deng, 2022. "Lung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Christopher W. Murray & Jennifer J. Brady & Mingqi Han & Hongchen Cai & Min K. Tsai & Sarah E. Pierce & Ran Cheng & Janos Demeter & David M. Feldser & Peter K. Jackson & David B. Shackelford & Monte M, 2022. "LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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