Open AccessNOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus
Author(s) -
Elise S. Demitrack,
Gail B. Gifford,
Theresa M. Keeley,
Nobukatsu Horita,
Andrea Todisco,
D. Kim Turgeon,
Christian W. Siebel,
Linda C. Samuelson
Publication year - 2017
Publication title -
american journal of physiology. gastrointestinal and liver physiology/american journal of physiology: gastrointestinal and liver physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.644
H-Index - 169
eISSN - 1522-1547
pISSN - 0193-1857
DOI - 10.1152/ajpgi.00325.2016
Subject(s) - notch signaling pathway , biology , microbiology and biotechnology , progenitor cell , stem cell , cell growth , receptor , cellular differentiation , signal transduction , genetics , gene
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.