Characterization of the Gastric Stem Cell Microenvironment and its Changes upon Infection with Helicobacter pylori

• Applicant: Professor Dr. Michael Sigal
• Subject Area: Gastroenterology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 287181577

Helicobacter pylori colonizes the stomachs of about 50% of the world population. Chronic colonization is the main risk factor for the development of gastric ulcers as well as gastric adenocarcinoma. We have recently demonstrated that the bacteria can directly interact with the long-lived stem cells in the stomach. We described a significant local increase in the number and proliferative activity of these cells upon colonization of gastric glands with H. pylori. The stem cells are located in the base of antral glands and regenerate the glands within 14 days. Infection-induced activation of stem cells almost doubles the turnover speed leading to development of gastric pathology. Relatively little is known about the regulation of stem cell activity in the stomach. Further, it is not known, how exactly H. pylori affects these processes. We hypothesize that the stem cell niche, which is composed of different cells that surround the stem cells, controls the activity of the stem cells. In the first part of the proposed project, we will focus on the Wnt signaling pathway in the stomach. Wnt is a central component of stem cell regulation in different organs and the stem cell marker Lgr5 is known to be a Wnt target gene. We will study, which cellular and molecular mechanisms control the level of activity of the Wnt signal in the stomach and determine its localization. Using genetically modified mice and the 3D gastric organoid model, we will identify the role of specific Wnt molecules for stem cell division, differentiation and glandular turnover. Next, we will study, how infection with H. pylori affects the Wnt signaling. We will identify bacterial virulence factors required for activation of stem cells and Wnt signaling. Further, we will manipulate the Wnt pathway to understand how this affects the development of gastric pathology. In the second part, we will characterize the transcriptome of the different cellular components of the stem cell niche in healthy stomach and upon infection with H. pylori. With this approach, we would like to find out, what type of niche cells controls the stem cell activity and how these cells change upon infection with H. pylori. We will perform functional experiments using the 3D-orgadoid models, where we will co-culture epithelial cells with the identified cells of interest, that can be further genetically modified. In summary, we would like to characterize the stem cell microenvironment under physiological as well as pathological conditions. We hope that our studies will improve the understanding of how bacteria may disrupt the homeostasis in the gastrointestinal mucosa leading to chronic diseases and malignant transformation.

• DFG Programme: Research Grants