Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells

点击翻译按钮获取中文摘要

Project Summary / Abstract The gastrin receptor, Cck2r, is a G-protein coupled receptor known to be expressed in the corpus in enterochromaffin-like (ECL) and parietal cells where it regulates acid secretion. However, it is also expressed in corpus progenitor cells and antral stem cells where it modulates their behavior in distinct ways. Recently, we have shown that Cck2r+ antral cells are self-renewing +4 stem cells that undergo predominant asymmetric cell division. However, in response to gastrin deficiency or carcinogenic injury, these antral stem cells shift to symmetric cell division and lineage trace more rapidly, indicating that gastrin acts to regulate Cck2r+ antral cell proliferation, and suggesting that antral G cells are niche cells. In contrast, we have shown that Cck2r+ corpus isthmal cells are ECL cell progenitors that respond to hypergastrinemia, which acts in a hormonal fashion to increase their proliferation and tracing, producing more ECL cells. Thus, we propose to study these two distinct Cck2r-expressing stomach progenitor cells and dissect more deeply their responses to gastrin stimulation through the following two Aims: Aim #1. What is the role of gastrin signaling in antral +4 stem cells? We will investigate the role of gastrin, both in vitro and in vivo, in modulating Cck2r+ antral stem cell responses to the major niche signals, R-spondin and Wnt, using adenovirally delivered agonists, and then validate antral gastrin (G) cells as true niche cells through targeted DTR ablation. We will investigate the response of Cck2r+ antral cells to both gastrin and carcinogens (MNU) using single cell RNA-sequencing. Aim #2. What is the role of gastrin signaling in corpus ECL cell progenitors? We propose to study the effects of long-term hypergastrinemia on Cck2r+ corpus progenitors, and also investigate the role of these isthmal progenitors in the response to corpus inflammation (H. pylori infection) and ulceration (acetic acid injury) with or without hypergastrinemia. Finally, we propose to characterize Cck2r+ corpus progenitors and their response to gastrin using single cell RNA-seq, in order to understand how gastrin may modulate the plasticity and longevity of corpus progenitors. Overall, these studies will seek to leverage the latest technologies to advance our understanding of the role of gastrin in modulating growth and regeneration of the stomach.