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

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...

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Autores principales:	Nobukatsu Horita, Theresa M. Keeley, Elise S. Hibdon, Elizabeth Delgado, Daniel Lafkas, Christian W. Siebel, Linda C. Samuelson
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Notch Signaling Stem Cell Niche Gastric Organoids Notch Inhibitory Antibodies LGR5 Stem Cells Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/c9c7c90acdba43d3b35b4515ca88e447
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spelling	oai:doaj.org-article:c9c7c90acdba43d3b35b4515ca88e4472021-11-14T04:34:14ZDelta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary2352-345X10.1016/j.jcmgh.2021.08.012https://doaj.org/article/c9c7c90acdba43d3b35b4515ca88e4472022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X2100179Xhttps://doaj.org/toc/2352-345XBackground & 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.Nobukatsu HoritaTheresa M. KeeleyElise S. HibdonElizabeth DelgadoDaniel LafkasChristian W. SiebelLinda C. SamuelsonElsevierarticleNotch SignalingStem Cell NicheGastric OrganoidsNotch Inhibitory AntibodiesLGR5 Stem CellsDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 275-287 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Notch Signaling Stem Cell Niche Gastric Organoids Notch Inhibitory Antibodies LGR5 Stem Cells Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Notch Signaling Stem Cell Niche Gastric Organoids Notch Inhibitory Antibodies LGR5 Stem Cells Diseases of the digestive system. Gastroenterology RC799-869 Nobukatsu Horita Theresa M. Keeley Elise S. Hibdon Elizabeth Delgado Daniel Lafkas Christian W. Siebel Linda C. Samuelson Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary
description	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.
format	article
author	Nobukatsu Horita Theresa M. Keeley Elise S. Hibdon Elizabeth Delgado Daniel Lafkas Christian W. Siebel Linda C. Samuelson
author_facet	Nobukatsu Horita Theresa M. Keeley Elise S. Hibdon Elizabeth Delgado Daniel Lafkas Christian W. Siebel Linda C. Samuelson
author_sort	Nobukatsu Horita
title	Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary
title_short	Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary
title_full	Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary
title_fullStr	Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary
title_full_unstemmed	Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary
title_sort	delta-like 1–expressing cells at the gland base promote proliferation of gastric antral stem cells in mousesummary
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/c9c7c90acdba43d3b35b4515ca88e447
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Delta-like 1–Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in MouseSummary

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