title: NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus.
abstract: The Notch signaling pathway is known to regulate stem cells and epithelial cell homeostasis in gastrointestinal tissues; however, Notch function in the corpus region of the stomach is poorly understood. In this study we examined the consequences of Notch inhibition and activation on cellular proliferation and differentiation and defined the specific Notch receptors functioning in the mouse and human corpus. Notch pathway activity was observed in the mouse corpus epithelium, and gene expression analysis revealed NOTCH1 and NOTCH2 to be the predominant Notch receptors in both mouse and human. Global Notch inhibition for 5 days reduced progenitor cell proliferation in the mouse corpus, as well as in organoids derived from mouse and human corpus tissue. Proliferation effects were mediated through both NOTCH1 and NOTCH2 receptors, as demonstrated by targeting each receptor alone or in combination with Notch receptor inhibitory antibodies. Analysis of differentiation by marker expression showed no change to the major cell lineages; however, there was a modest increase in the number of transitional cells coexpressing markers of mucous neck and chief cells. In contrast to reduced proliferation after pathway inhibition, Notch activation in the adult stomach resulted in increased proliferation coupled with reduced differentiation. These findings suggest that NOTCH1 and NOTCH2 signaling promotes progenitor cell proliferation in the mouse and human gastric corpus, which is consistent with previously defined roles for Notch in promoting stem and progenitor cell proliferation in the intestine and antral stomach.
  Here we demonstrate that the Notch signaling pathway is essential for proliferation of stem cells in the mouse and human gastric corpus. We identify NOTCH1 and NOTCH2 as the predominant Notch receptors expressed in both mouse and human corpus and show that both receptors are required for corpus stem cell proliferation. We show that chronic Notch activation in corpus stem cells induces hyperproliferation and tissue hypertrophy, suggesting that Notch may drive gastric tumorigenesis.
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, Michigan.
authors.forename: Elise S
authors.initials: ES
authors.lastname: Demitrack
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, Michigan.
authors.forename: Gail B
authors.initials: GB
authors.lastname: Gifford
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, Michigan.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Keeley
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, Michigan.
authors.forename: Nobukatsu
authors.initials: N
authors.lastname: Horita
authors.affiliation: Department of Internal Medicine, The University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Todisco
authors.affiliation: Department of Internal Medicine, The University of Michigan, Ann Arbor, Michigan; and.
authors.forename: D Kim
authors.initials: DK
authors.lastname: Turgeon
authors.affiliation: Department of Discovery Oncology, Genentech, Incorporated, San Francisco, California.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Siebel
authors.affiliation: Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, Michigan; lcsam@umich.edu.|Department of Internal Medicine, The University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D005753:Gastric Mucosa / Q000166:cytology; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D051379:Mice; D009940:Organoids / Q000166:cytology / Q000502:physiology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells; D013270:Stomach / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D051881:Receptor, Notch1; D051883:Receptor, Notch2; D013629:Tamoxifen
keywords: SOX2; cellular differentiation; gastric organoids; gastric stem cells; spasmolytic polypeptide expressing metaplasia (SPEM)