Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in Mouse
| Autor: | Elise S. Hibdon, Elizabeth Delgado, Nobukatsu Horita, Theresa M. Keeley, Daniel Lafkas, Linda C. Samuelson, Christian W. Siebel |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
JAG2
JAG1 Notch Inhibitory Antibodies LGR5 Stem Cells Notch signaling pathway RC799-869 Mice Pyloric Antrum Organoid Animals Receptor Notch1 Stem Cell Niche fl floxed Receptor Cellular localization Cell Proliferation Original Research GFP green fluorescent protein Notch Signaling DLL Delta-like Receptors Notch Hepatology Chemistry Stem Cells Calcium-Binding Proteins Gastric Organoids digestive oral and skin physiology Gastroenterology LGR5 JAG Jagged Diseases of the digestive system. Gastroenterology Cell biology Editorial TX tamoxifen Stem cell |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 275-287 (2022) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims 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. Methods 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. Results 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. Conclusions 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. Graphical abstract |
| Databáze: | OpenAIRE |
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