Common diseases such as indigestion and heartburn, as well as peptic ulcers, autoimmune gastritis, and stomach and esophageal cancer have something in common. – They involve alterations in the normal activity of the stomach’s parietal cells (PCs), the only cells in the body that produce acid. Despite their medical importance, little is known about the molecular and genetic pathways that direct the generation and maturation of PCs from stem cells.
Aiming to gain new insights into PC generation, researchers at Baylor College of Medicine and collaborating institutions identified genes that emerging PCs preferentially expressed to guide their development. They discovered a “training program” that drives the development of PCs from stem cells and their subsequent maturation into active acid-secreting cells. Published in cell stem cellThe findings may lead to new strategies to regulate PC function in different disease settings.
“PCs secrete hydrochloric acid, which creates a strongly acidic environment in the stomach with beneficial effects, such as killing bacteria in contaminated foods, facilitating the digestion of food, and promoting the absorption of minerals such as phosphate, calcium, and iron. But acid also can be dangerous, causing conditions ranging from reflux to peptic ulcers and life-threatening gastric bleeding,” said corresponding author Dr. Jason Mills, Herman Brown Professor of Medicine and Gastroenterology and co-director of the Disease Center. Digestive Medicine (DDC) at the Texas Medical Center at Baylor.
Studying how these cells are generated can help scientists understand the conditions under which the stomach stops producing PC, resulting in an acid-free stomach that promotes gastric cancer. Or the opposite, conditions in which the stomach produces too much PC and too much acid.
“Our first step was to generate enough PCs to study their development and maturation,” said study co-first author Dr. Mahliyah Adkins-Threats, a graduate student in Mills’ lab while working on this project. “PCs have a long lifespan (about two months), so we needed a system that would allow us to characterize the differentiation process of PCs in a shorter time.”
The researchers worked with a mouse model in which they removed the existing PCs. “This triggered the production of new cells in which we were able to capture the first look at the molecular and morphological steps involved when cells in the gastric epithelium commit to becoming PCs and then mature,” Adkins-Threats said.
Using single-cell RNA sequencing, a technique to identify the genes expressed by a cell, the team identified which genes the cells turned on or off as they became more mature PCs.
The researchers found that of all the genes expressed by the cells, there was one, estrogen-related receptor gamma (ERRγ), a gene involved in regulating cellular metabolism, that was expressed in both very young parietal cells and fully functional parietal cells. ERRγ was sufficient for cells to become PCs.
“The progenitor PC cells that were committed to expressing ERRγ were destined to eventually become mature PCs,” said Mills, a member and associate co-director of cancer education at the Dan L Duncan Comprehensive Cancer Center. “Our findings indicate that ERRγ is responsible for regulating the differentiation and maturation of these acid-secreting PCs.”
“It is important to note that when we eliminate the Esrrg gene in gastric epithelium, “Entire gastric sections completely lacked PC lineage cells, indicating that this gene is not only sufficient but also necessary for stem cells to commit to the PC lineage,” Adkins-Threats said. “We view ERRγ as the ‘trainer’ of these young stem cells. ; “It is the only gene that orchestrates the dynamics of metabolic pathways that shape stem cells into fully mature PCs.”
Co-first author Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y. Hwang, Joseph R. Burclaff, and Shilpa Jain also contributed to this work. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Washington University atSt. Louis, the University of North Carolina at Chapel Hill, North Carolina State University, University of Texas Health at San Antonio and Cincinnati Children’s Hospital Medical Center.
This study was supported by the following grants: National Science Foundation Graduate Research Fellowship Program DGE-2139839/1745038, as well as multiple grants from the National Institutes of Health including: T32 DK077653, T32 GM007067, a pilot grant from NIDDK DDC (P30 DK56338), NIDDK R01 DK094989 and DK110406 and NCI R01 CA239645.