Original ResearchBasic and Translational—Alimentary TractGPR30-Expressing Gastric Chief Cells Do Not Dedifferentiate But Are Eliminated via PDK-Dependent Cell Competition During Development of Metaplasia
Graphical abstract
Section snippets
Mice
Mist1-CreERT,13 Lgr5-DTR-GFP,24 Lox-STOP-Lox(LSL)-KrasG12D,13 LSL-HrasG12V-IRES-GFP,25 and LSL-GFP26 mice were previously described. R26 transgenic mice, Kitl-GFP mice, and Gpr30-knockout mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Gpr30-rtTA mice and TetO-KrasG12D mice were generated as described in the Supplementary Methods and Supplementary Figure 2. Mouse and in vitro culture experiments were repeated at least twice, with at least 2 biological replicates per group. All
Gpr30 Is Specifically Expressed in Gastric Chief Cells
To identify chief cell–specific genes, we performed transcriptome analyses using fluorescence-activated sorted cells isolated from Mist1-CreERT;R26-TdTomato mice with or without depletion of Lgr5+ chief cells (see Supplementary Methods). TdTomato+ Mist1-expressing cells were sorted from mice 2 days after tamoxifen induction and were designated as the chief cell–enriched group, whereas TdTomato+ cells sorted from induced Mist1-CreERT;Lgr5-DTR-EGFP;R26-TdTomato mice treated with diphtheria toxin
Discussion
Chief cells attracted considerable attention after a number of studies suggested they might be the cellular origin of cancer and precancerous metaplasia.7,12,23 However, this proposed model of chief cell transdifferentiation/dedifferentiation rested largely on 2 major observations: namely, lineage-tracing events in CreERT mice and coexpression of neck cell markers with chief cell markers on immunostaining. There are several critical limitations to lineage-tracing experiments, including the
CRediT Authorship Contributions
Masahiro Hata, MD (Data curation: Lead; Formal analysis: Lead; Validation: Lead;
Visualization: Lead). Hiroto Kinoshita, MD, PhD (Data curation: Lead; Formal analysis: Lead;
Visualization: Lead). Yoku Hayakawa, MD, PhD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead;
Supervision: Lead; Validation: Supporting; Visualization: Supporting; Writing – original
draft: Lead; Writing – review & editing: Lead). Mitsuru
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2023, International Immunopharmacologyp57<sup>Kip2</sup> imposes the reserve stem cell state of gastric chief cells
2022, Cell Stem CellCitation Excerpt :The upregulated genes at 1 dpi showed a significant enrichment for genes upregulated in SPEM cells (Nozaki et al., 2008) as well as genes in a cell proliferation-related gene set and related GO terms (Figures 1D, 1E, and S1B). Downregulated genes at 1dpi showed high enrichment for genes commonly upregulated in quiescent stem cells (QSCs) (quiescent hematopoietic stem cells, muscle stem cells, and hair follicle stem cells) (Cheung and Rando, 2013) and genes expressed in gastric chief cells from three different reference sets (Busslinger et al., 2021 for Figure S1C; Hata et al., 2020 for Figure 1D; Pgc+ scRNA-seq from Figure 2 for Figure S1D) (Figures 1D, 1E, S1C, and S1D; Table S2). On the other hand, the intestinal stem cell (ISC) signature genes (Muñoz et al., 2012) showed no significant enrichment (Figure 1D; Table S2), and markers of RSCs such as Troy and Lgr5 did not change more than 2-fold in either direction (Figure 1E), indicating that the expression patterns of stem cell-related genes are fairly stable in gastric chief cells during injury repair.
Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond
2022, GastroenterologyCitation Excerpt :Moreover, several studies have shown that SPEM can arise in the absence of any proliferation, which would preclude the 1–2 isthmal stem cells per gland giving rise to 10+ SPEM cells within a few days.40,42,45,68 More recently, Hata et al79 suggested that acute parietal cell loss leads to apoptosis among chief cells marked with GPR30 or Mist1 driver mice and that not all such chief cells make it to SPEM cells. These results do not actually conflict with data from other laboratories, as varying degrees of injury cause varying degrees of conversion of chief cells to SPEM cells, depending on the age of mice and of chief cells.68
Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus
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Conflicts of interest The authors disclose no conflicts.
Funding Yoku Hayakawa is supported by the KAKENHI Grant-in-Aid for Scientific Research (17K09347 and 17H05081), Project for Cancer Research and Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and development (AMED), Pharmacological Research Foundation, research grant of Bristol-Myers Squibb, Kowa Life Science Foundation, Senshin Medical Research Foundation, Yokoyama Clinical Pharmacological Research Foundation, Kanae Foundation of the Promotion of Medical Science, Inoue Science Research Award, and Takeda Science Foundation Visionary Research Grant, Princess Takamatsu Cancer Research Fund, and Advanced Research and Development Programs for Medical Innovation. Mitsuru Konishi is supported by the research grant from the Institute for Adult Diseases, Asahi Life Foundation. Timothy C. Wang received the National Institutes of Health grants (R35CA210088 and 5U01DK103155-04).
Author names in bold designate shared co-first authorship.
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Authors share co-first authorship.