Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in Mouse

Notch pathway signaling maintains gastric epithelial cell homeostasis by regulating stem cell proliferation and differentiation. We previously identified NOTCH1 and NOTCH2 as the key Notch receptors controlling gastric stem cell function. Here, we identify the niche cells and critical Notch ligand r...

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Bibliographic Details
Published in:Cellular and molecular gastroenterology and hepatology 2022-01, Vol.13 (1), p.275-287
Main Authors: Horita, Nobukatsu, Keeley, Theresa M., Hibdon, Elise S., Delgado, Elizabeth, Lafkas, Daniel, Siebel, Christian W., Samuelson, Linda C.
Format: Article
Language:English
Subjects:
Animals
Calcium-Binding Proteins - physiology
Cell Proliferation
Gastric Organoids
LGR5 Stem Cells
Mice
Notch Inhibitory Antibodies
Notch Signaling
Original Research
Pyloric Antrum - metabolism
Receptor, Notch1 - genetics
Receptor, Notch1 - metabolism
Receptors, Notch - metabolism
Stem Cell Niche
Stem Cells - metabolism
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Summary:Notch pathway signaling maintains gastric epithelial cell homeostasis by regulating stem cell proliferation and differentiation. We previously identified NOTCH1 and NOTCH2 as the key Notch receptors controlling gastric stem cell function. Here, we identify the niche cells and critical Notch ligand responsible for regulating stem cell proliferation in the distal mouse stomach. Expression of Notch ligands in the gastric antrum was determined by quantitative reverse-transcriptase polymerase chain reaction and cellular localization was determined by in situ hybridization and immunostaining. The contribution of specific Notch ligands to regulate epithelial cell proliferation in adult mice was determined by inducible gene deletion, or by pharmacologic inhibition using antibodies directed against specific Notch ligands. Mouse gastric organoid cultures were used to confirm that Notch ligand signaling was epithelial specific. Delta-like 1 (DLL1) and Jagged 1 (JAG1) were the most abundantly expressed Notch ligands in the adult mouse stomach, with DLL1 restricted to the antral gland base and JAG1 localized to the upper gland region. Inhibition of DLL1 alone or in combination with other Notch ligands significantly reduced epithelial cell proliferation and the growth of gastric antral organoids, while inhibition of the other Notch ligands, DLL4, JAG1, and JAG2, did not affect proliferation or organoid growth. Similarly, DLL1, and not DLL4, regulated proliferation of LGR5+ antral stem cells, which express the NOTCH1 receptor. DLL1 is the key Notch ligand regulating epithelial cell proliferation in the gastric antrum. We propose that DLL1-expressing cells at the gland base are Notch niche cells that signal to adjacent LGR5+ antral stem cells to regulate stem cell proliferation and epithelial homeostasis. [Display omitted]
ISSN:2352-345X
2352-345X
DOI:10.1016/j.jcmgh.2021.08.012