Abstract | BACKGROUND & AIMS: Enterochromaffin-like (ECL) cells in the stomach express gastrin/ cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified. METHODS: RESULTS: Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2+ isthmus progenitors, but not Hdc+ mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r+Hdc- cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro. CONCLUSIONS:
|
Authors | Weiwei Sheng, Ermanno Malagola, Henrik Nienhüser, Zhengyu Zhang, Woosook Kim, Leah Zamechek, Antonia Sepulveda, Masahiro Hata, Yoku Hayakawa, Chun-Mei Zhao, Duan Chen, Timothy C Wang |
Journal | Cellular and molecular gastroenterology and hepatology
(Cell Mol Gastroenterol Hepatol)
Vol. 10
Issue 2
Pg. 434-449.e1
( 2020)
ISSN: 2352-345X [Electronic] United States |
PMID | 32330731
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Gastrins
- Receptor, Cholecystokinin B
|
Topics |
- Animals
- Disease Models, Animal
- Enterochromaffin-like Cells
(metabolism, pathology)
- Gastric Mucosa
(cytology, metabolism, pathology)
- Gastrins
(blood, metabolism)
- Humans
- Hyperplasia
(blood, pathology)
- MAP Kinase Signaling System
- Mice
- Receptor, Cholecystokinin B
(metabolism)
- Stem Cells
(pathology)
|