Common conditions such as indigestion, heartburn, peptic ulcers, autoimmune gastritis, and stomach and esophageal cancers share a common factor – they involve disruptions of the normal activity of parietal cells (PCs) in the stomach. These are the only cells in the body that produce acid. Despite their medical significance, little is known about the molecular and genetic pathways that guide the generation and maturation of PCs from stem cells.
Researchers at Baylor College of Medicine and collaborating institutions have made strides in understanding this process. They identified genes preferentially expressed by emerging PCs to guide their development. This led to the discovery of a 'training program' driving PC development from stem cells and subsequent maturation into active acid-secreting cells. The findings, published in Cell Stem Cell, could lead to new strategies to regulate PC function in different disease settings.
“PCs secrete hydrochloric acid, which generates the strongly acidic environment in the stomach with beneficial effects," said corresponding author Dr. Jason Mills. He explained that these benefits include killing bacteria in contaminated food, facilitating food digestion, and promoting absorption of minerals including phosphate, calcium, and iron. However, excess acid can be dangerous, causing conditions ranging from reflux to life-threatening gastric bleeds.
Understanding how these cells are generated can help scientists understand conditions where the stomach stops making PCs - resulting in an acid-free stomach that promotes gastric cancer - or conversely where it makes too many PCs and too much acid.
The researchers worked with a mouse model where they eliminated existing PCs. "This triggered the production of new cells," said co-first author Dr. Mahliyah Adkins-Threats. Using single-cell RNA sequencing techniques allowed them to identify what genes were being turned on or off as they matured into PCs.
Of all the genes expressed by these cells, one stood out: estrogen-related receptor gamma (ERRγ), a gene involved in regulating cell metabolism. ERRγ was expressed in both very young parietal cells and in fully functional parietal cells, and was sufficient for the cells to develop into PCs.
"Progenitor PC cells that were committed to expressing ERRγ, were destined to eventually become mature PCs," said Mills. "Our findings indicate that ERRγ is responsible for regulating the differentiation and maturation of these acid-secreting PCs."
When the Esrrg gene was deleted in the gastric epithelium, whole gastric sections completely lacked any PC lineage cells. "We see ERRγ as the 'trainer' of these young stem cells; it's the one gene that orchestrates the dynamics of the metabolic pathways that shape stem cells into fully mature PCs," Adkins-Threats said.
The study was supported by several grants from the National Science Foundation-Graduate Research Fellowship Program and multiple grants from the National Institutes of Health.
