Researchers have discovered the molecular and genetic pathways that control the development and maturation of parietal cells, which are responsible for producing stomach acid, from stem cells. These findings could lead to new approaches for regulating parietal cell function in various diseases such as autoimmune gastritis, stomach cancer, and esophageal cancer. Common conditions like indigestion, heartburn, peptic ulcers, and autoimmune gastritis are all linked to disturbances in the normal activity of parietal cells.
Stomach parietal cells (PCs) are the only cells in the body that produce acid. However, very little is known about the molecular and genetic pathways involved in the creation and growth of PCs from stem cells, despite their medical significance.
Seeking to gain a better understanding of the development of PCs, a team of researchers at Baylor College of Medicine and other institutions identified the genes that were preferentially expressed by emerging PCs to help guide their growth. They uncovered a ‘training program’ that directs the development of PCs from stem cells and their subsequent maturation into actively acid-secreting cells. Their findings were published in Cell Stem Ce.The results could help develop new approaches to manage PC function in various medical conditions. PCs produce hydrochloric acid, which creates the highly acidic environment in the stomach. This acidity has positive effects, such as eliminating bacteria in tainted food, aiding in food digestion, and enhancing the absorption of minerals like phosphate, calcium, and iron. However, acid can also be harmful, leading to conditions ranging from acid reflux to peptic ulcers to potentially life-threatening gastric bleeds, as explained by Dr. Jason Mills, the corresponding author and Herman Brown Endowed Professor of medicine — gastroenterology and co-director of the Texas Medi.Digestive Disease Center (DDC) at Baylor’s Center Digestive Disease Center (DDC) has been studying the generation of cells to better understand stomach conditions. The goal is to understand the process that leads to the stomach stopping the production of PCs. This can result in an acid-free stomach, which can lead to gastric cancer. Conversely, the study also aims to understand conditions where the stomach produces too many PCs and too much acid.
Dr. Mahliyah Adkins-Threats, a graduate student in the Mills lab, explained that the first step was to generate enough PCs to study their development and maturation. Since PCs are long-lived, lasting around two months, a system was needed to facilitate the study.The researchers aimed to understand the process of PC differentiation in a shorter time period. They used a mouse model to remove existing PCs, which led to the generation of new cells. This allowed them to observe the molecular and morphological changes involved as cells in the gastric epithelium transitioned into PCs and matured. By utilizing single-cell RNA sequencing, the team was able to determine the genes being activated or deactivated as the cells matured into PCs.It was found that among all the genes expressed by the cells, there was one called estrogen-related receptor gamma (ERRγ), which is involved in controlling cell metabolism, that was present in both very young parietal cells and fully functional parietal cells. ERRγ was enough for the cells to develop into parietal cells (PCs).
“Progenitor PC cells that were committed to expressing ERRγ, were destined to eventually become mature PCs,” said Mills, a member and co-associate director for cancer education at the Dan L Duncan Comprehensive Cancer Center. “Our findings indicate that ERRγ is responsible for regulating the differentiation and maturation of the cells.”The acid-secreting parietal cells (PCs) are critical for the normal functioning of the stomach. When the Esrrg gene was removed from the gastric epithelium, there was a complete absence of PC lineage cells in the gastric sections. This indicates that the Esrrg gene is not only important but also necessary for stem cells to develop into PC lineage cells. According to Adkins-Threats, ERRγ acts as a “trainer” for these young stem cells, playing a pivotal role in shaping them into fully mature PCs by orchestrating their metabolic pathways. The study was co-authored by Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y. Hwang, Joseph R. Burclaff, and Shilp.A Jain also contributed to this study. The authors are associated with institutions such as Baylor College of Medicine, Washington University at St. Louis, 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 research received support from grants including the National Science Foundation-Graduate Research Fellowship Program DGE-2139839/1745038 and various grants from the National Institutes of Health such as T32 DK077653, T32 GM007067, a pilot award from the NIDDK-funded DDC (P30 DK56338), and NIDDK R01.DK094989 and DK110406 and NCI R01 CA239645.
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