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

Nature Cell Biology volume 19, pages 774–786 (2017)Cite this article

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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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Figure 1: Lgr5 is selectively expressed in a subpopulation of chief cells at the base of mouse and human corpus glands.
Figure 2: Lgr5-expressing chief cells express gastric stem cell markers.
Figure 3: Lgr5-cell ablation impairs epithelial homeostasis in the corpus.
Figure 4: Lgr5-expressing chief cells do not function as stem cells during homeostasis of the adult corpus epithelium.
Figure 5: Lgr5-expressing chief cells drive epithelial regeneration in response to tissue damage.
Figure 6: Damage-inducible modulation of WNT pathway genes during Lgr5+ chief cell activation.
Figure 7: Gastric cancer originates from Lgr5-expressing chief cells.
Figure 8: LGR5 is co-expressed with stem/Wnt markers in human gastric cancer.

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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 (A∗STAR), the Singapore Gastric Cancer Consortium (SGCC) and the National Research Foundation (NRF) NRFI2017-03.

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Author notes

  1. Si Hui Tan, Angeline Wong and Yada Swathi: These authors contributed equally to this work.

Authors and 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.

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Integrated supplementary information

Supplementary Figure 1 Histological analysis of Lgr5+ corpus cells.

(a) ISH for DapB (negative control) GIF, Muc6 and Muc5ac on mouse corpus tissue (image representative of 5 repeats). (b) Co-ISH for DapB (negative control) (image representative of 5 repeats). (c) Co-ISH for Lgr5 together with GIF and Mist1 (image representative of 5 repeats). (d) IHC for Lgr5-driven EGFP on gastric corpus and antral tissue using Lgr5-EGFP-ires-CreERT2(upper panel) or Lgr5-DTR-EGFP (lower panel) (image representative of 5 repeats). (e) Co-IF for EGFP and MUC5AC on Lgr5-DTR-EGFP gastric corpus tissue (image representative of 5 repeats). Scale bars represent 50 μm.

Supplementary Figure 2 Characterization of Lgr5-expressing corpus cells.

(a) EGFP FACS profile of single corpus cells from Lgr5-DTR-EGFP mice and wildtype animals (n = 3). (b) Cytospin of sorted Lgr5-GFPhigh cells from Lgr5-DTR-EGFP mice stained for GFP and GIF (Image representative of 3 repeats). Scale bar represents 5 μm. (c) Hierarchical clustering of 1832 genes that were differentially expressed by more than 2-fold in the Lgr5-GFPhigh population when compared to their Lgr5-GFPneg counterpart (n = 3). (d) ISH for Sostdc1 on mouse antral and small intestinal tissue (image representative of 3 repeats). Scale bars represent 50 μm. (e) Sostdc1 qPCR analysis on mouse corpus, antral, small intestinal and colon tissue (n = 3). Error bars represented as mean ± s.e.m.

Supplementary Figure 3 Lgr5+ cell-ablation in the stomach.

(a) Experimental strategy to ablate Lgr5-expressing cells using the Lgr5-DTR-EGFP mouse model. (b) Histological analysis of the corpus tissue from Lgr5-DTR-EGFP mice and control treated animals at 24 h post DT administration (image representative of 3 repeats). (c) Experimental strategy to ablate Lgr5-expressing cells over a 3 week period using Lgr5-DTR-EGFP mice and control animals. (d) IF for KI67 and CDH1 on Lgr5-cell ablated corpus tissue from Lgr5-DTR-EGFP mice and wildtype-control animals described in c (image representative of 3 repeats). (e) Experimental strategy to ablate Lgr5-expressing cells over a 3 week period followed by a 3 week recovery phase using Lgr5-DTR-EGFP mice and control animals. (f) Histological analysis of the corpus epithelium from Lgr5-DTR-EGFP mice and wildtype control animals described in e (image representative of 3 repeats). (g) Experimental strategy to ablate Lgr5-expressing cells over a 4-day period (n = 3). (h) qPCR analysis for Lgr5, Troy, Mist1 and Sox2 in corpus tissue from Lgr5-DTR-EGFP mice and wildtype control animals described in g (n = 3). (i) The aberrant morphology of the corpus epithelium in Lgr5+ cell-depleted tissue mirrors altered characteristics induced by acute reduction of the peptide hormone gastrin that typically stimulates parietal cells to secrete gastric acid42,43. Gastrin producing G-cells reside along the Lgr5-cell stem cell zone in the lower compartment of antral glands. Given the spatial overlap of antral Lgr5+ and gastrin-producing G cells, we sought to determine if Lgr5-cell ablation would affect antral G cells, which could in turn influence the corpus epithelium. IF for gastrin in antral tissue from Lgr5-DTR-EGFP mice and wildtype control animals described in g (image representative of 3 repeats). (j) Quantification of Gastrin+ cells described in i (n = 3). Data were tested for significance by an unpaired two-tailed t-test. P-values of statistical significance are represented as ∗∗∗P < 0.001,∗∗P < 0.01, ∗P < 0.05. Scale bars represent 50 μm; error bars represented as mean ± s.e.m.

Supplementary Figure 4 Strategy to knock-in the 2A-CreERT2 cassette into the Lgr5 locus.

(a) Schematic structure of the 2A-CreERT2 cassette knocked into the mouse Lgr5 gene locus. (b) Lgr5-derived lineage tracing in the antrum, small intestine and colon using Lgr5-2A-CreER-T2tg/+/R26R-tdTomatotg/+ mice at 12 h and 14 days post tamoxifen induction (image representative of 3 repeats). (c) Lgr5-derived lineage tracing at 6 months as described in (b) in the antrum, small intestine and colon (image representative of 3 repeats). Scale bars represent 50 μm.

Supplementary Figure 5 Lgr5+ cell-derived RFP+ cell clusters do not expand under homeostatic conditions.

(a) RFP+ cluster analysis in corpus glands from Lgr5-2A-CreER-T2tg/+/R26R-tdTomatotg/+ mice at 2 days, 14 days, 3 months and 6 months post tamoxifen administration (0.1 mg g−1 body weight) (n = 3 for each time point). (b) IF for H-K-ATPase on corpus sections from wildtype animals treated with low dose (0.1 mg g−1 body weight) or high-dose (0.27 mg g−1 body weight) tamoxifen at 2 days post induction (image representative of 3 repeats). (c) IHC for EGFP on corpus sections from Lgr5-DTR-EGFP animals treated with high-dose (0.27 mg g−1 body weight) tamoxifen at 2 days post induction (image representative of 3 repeats). (d) IF for H-K-ATPase and TFF2 on corpus sections from Lgr5-2A-CreER-T2tg/+/R26R-tdTomatotg/+ mice treated with high-dose (0.27 mg g−1 body weight) tamoxifen at 14 days, 3 months and 6 months post administration (image representative of 3 repeats). Scale bar represents 50 μm; error bars represented as mean ± s.e.m.

Supplementary Figure 6 Lgr5+ cell-derived RFP+ cell clusters expand post injury.

(a) RFP+ cluster analysis in corpus glands from Lgr5-2A-CreER-T2tg/+/R26R-tdTomatotg/+ mice at 2 days, 14 days, 3 months and 6 months post tamoxifen administration (0.27 mg g−1 body weight) (n = 3 for each time point). b, Lgr5-EGFP FACS profile of single corpus cells from Lgr5-DTR-EGFP mice (n = 5). (c) Corpus organoid formation efficiency of sorted Lgr5-GFPpos. and GFPneg. cells (n = 10). (d) Representative example of a developing corpus organoid derived from a single Lgr5-GFPhigh corpus cell (n = 10). (e) Experimental strategy to analyze the differentiation capacity of Lgr5-cell derived organoids in response to growth factor withdrawal (n = 3 for each time point). (f) qPCR analysis for Lgr5, Axin2 and Muc5ac in Lgr5-derived organoids cultured in normal (ENRGFW) medium and medium containing only EGF, Rspondin and Gastrin (ERG) (n = 3). Data were tested for significance by an unpaired two-tailed t-test. P-values of statistical significance are represented as ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. Scale bars represent 50 μm; error bars represented as mean ± s.e.m.

Supplementary Figure 7 Damaged-induced differential gene expression during Lgr5+ chief cell activation.

(a) Venn diagram illustrating overlapping genes differentially expressed in tamoxifen-treated Lgr5-GFPhigh cells compared to non-treated Lgr5-GFPhigh control cells and genes that were differentially expressed between tamoxifen-treated Lgr5-GFPhigh/low and tamoxifen-treated Lgr5-GFPneg cells (n = 3). (b) qPCR for Mmp7 and Sostdc1 on corpus tissue samples from wildtype animals treated with high-dose (0.27 mg g−1 body weight) tamoxifen at 24 h post induction (n = 3). (c) ISH for Lgr5, Mmp7 and Sostdc1on corpus tissue sections from wildtype animals treated with high-dose (0.27 mg g−1 body weight) tamoxifen at 48 h post induction (image representative of 3 repeats). d , ISH for DapB (negative control) on corpus tissue sections from wildtype animals treated with high-dose (0.27 mg g−1 body weight) tamoxifen at 24 and 48 h post induction (image representative of 3 repeats). (e) Doxycycline-inducible Synthesized Mmp7 plasmid map and qPCR analysis for Mmp7 (synthesized) in Mmp7 transfected Lgr5+ cell-derived corpus organoids at 3 days post doxycycline administration (n = 3). (f) Doxycycline-inducible Synthesized Sostdc1 plasmid map and qPCR analysis for Sostdc1 (synthesized) in Sostdc1 transfected Lgr5-cell derived corpus organoids at 3 days post doxycycline administration (n = 3). Data were tested for significance by an unpaired two-tailed t-test. P-values of statistical significance are represented as ∗∗∗P < 0.001, ∗∗P < 0.01, ∗P < 0.05. Scale bars represent 50 μm; error bars represented as mean ± s.e.m.

Supplementary Figure 8 Histology on cancer and control corpus tissue.

(a) Experimental strategy to induce control animals (LSL-Kras(G12D)tg/+). (b) IHC staining for Phospho-MAPK, KI67, MUC5AC, TFF2 and H-K-ATPase on control (LSL-Kras(G12D)tg/+) corpus sections at 4 months post-tamoxifen induction (image representative of 3 repeats). (c) Experimental strategy to induce Lgr5-driven active Kras(G12D) expression. (d) IF staining for CDH1, VIMENTIN and GIF on (Lgr5-2A-CreER-T2tg/+/LSL-Kras(G12D)tg/+) corpus sections at 4 months post-tamoxifen induction (image representative of 3 repeats). (e) IHC analysis on ‘normal’ human corpus tissue (image representative of 3 repeats). (f) ISH for DapB (negative control) on human corpus tumor tissue (image representative of 3 repeats). g, Co-ISH for DapB (negative control) on human corpus tumor tissue (image representative of 3 repeats). Scale bars represent 50 μm.

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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). (AVI 5430 kb)

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). (AVI 8159 kb)

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). (AVI 14641 kb)

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). (AVI 13821 kb)

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Leushacke, M., Tan, S., Wong, A. et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol 19, 774–786 (2017). https://doi.org/10.1038/ncb3541

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