Article | Published:

Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach

Nature Cell Biology volume 19, pages 774786 (2017) | Download Citation

Abstract

The daily renewal of the corpus epithelium is fuelled by adult stem cells residing within tubular glands, but the identity of these stem cells remains controversial. Lgr5 marks homeostatic stem cells and ‘reserve’ stem cells in multiple tissues. Here, we report Lgr5 expression in a subpopulation of chief cells in mouse and human corpus glands. Using a non-variegated Lgr5-2A-CreERT2 mouse model, we show by lineage tracing that Lgr5-expressing chief cells do not behave as corpus stem cells during homeostasis, but are recruited to function as stem cells to effect epithelial renewal following injury by activating Wnt signalling. Ablation of Lgr5+ cells severely impairs epithelial homeostasis in the corpus, indicating an essential role for these Lgr5+ cells in maintaining the homeostatic stem cell pool. We additionally define Lgr5+ chief cells as a major cell-of-origin of gastric cancer. These findings reveal clinically relevant insights into homeostasis, repair and cancer in the corpus.

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Acknowledgements

We thank S. Mustafah and the SIgN Flow Facility for FACS assistance, G. Wright, J. Lim and S. Zulkifli for imaging assistance, and A. Fatehullah, C. Leung and R. Seishima for their technical expertise and manuscript proofreading. We also thank Y. Khay Guan and J. So for providing the human material, and D. H. Alpers, Washington University School of Medicine for providing the Gastric Intrinsic Factor antibody. We thank S. Srivastava for analysing and confirming a SPEM phenotype of Lgr5-cell-derived corpus metaplasia. In addition, we thank F. Sauvage, Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA for providing the Lgr5-DTR-EGFP mice. M.L. is supported by the National Medical Research Council (NMRC) Singapore. N.B. is supported by the Agency for Science, Technology and Research (ASTAR), the Singapore Gastric Cancer Consortium (SGCC) and the National Research Foundation (NRF) NRFI2017-03.

Author information

Author notes

    • Si Hui Tan
    • , Angeline Wong
    •  & Yada Swathi

    These authors contributed equally to this work.

Affiliations

  1. A*STAR Institute of Medical Biology, 138648, Singapore

    • Marc Leushacke
    • , Si Hui Tan
    • , Angeline Wong
    • , Yada Swathi
    • , Amin Hajamohideen
    • , Liang Thing Tan
    • , Jasmine Goh
    • , Esther Wong
    • , Simon L. I. J. Denil
    •  & Nick Barker
  2. Cancer Research Institute, Kanazawa University, Kakuma-machi Kanazawa 920-1192, Japan

    • Kazuhiro Murakami
    •  & Nick Barker
  3. Centre for Regenerative Medicine, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

    • Nick Barker

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Contributions

M.L. designed, performed experiments, analysed data and wrote the manuscript. S.H.T. performed FACS and microarray experiments, bioinformatics analyses and wrote the manuscript. A.W., L.T.T. and J.G. performed histology, FACS and organoid experiments. K.M. generated inducible expression constructs and performed organoid experiments. Y.S. performed microarray experiments and generated the Lgr5-2A-CreERT2 mouse line. A.H. performed histology experiments. S.L.I.J.D. performed bioinformatics analyses. E.W. generated the Lgr5-2A-CreERT2 mouse line. N.B. supervised the project, generated the Lgr5-2A-CreERT2 mouse line, analysed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nick Barker.

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Videos

  1. 1.

    Long-term ablation of Lgr5-expressing chief cells (xy-plane).

    xy-plane imaging of wholemount corpus tissue from Lgr5-DTR-EGFP mice after 3 weeks of sustained DT administration (β-catenin staining to demarcate cell boundaries in white, nuclear staining using DAPI in blue).

  2. 2.

    Control-treated corpus tissue (xy-plane).

    xy-plane imaging of wholemount corpus tissue from wildtype mice after 3 weeks of sustained DT administration (β-catenin staining to demarcate cell boundaries in white, nuclear staining using DAPI in blue).

  3. 3.

    Long-term ablation of Lgr5-expressing Chief Cells (xz-plane).

    xz-plane imaging of wholemount corpus tissue from Lgr5-DTR-EGFP mice after 3 weeks of sustained DT administration (β-catenin staining to demarcate cell boundaries in white, nuclear staining using DAPI in blue).

  4. 4.

    Control-treated Corpus Tissue (xz-plane).

    xz-plane imaging of wholemount corpus tissue from wildtype mice after 3 weeks of sustained DT administration (β-catenin staining to demarcate cell boundaries in white, nuclear staining using DAPI in blue).

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DOI

https://doi.org/10.1038/ncb3541

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