Common conditions such as indigestion and heartburn, as well as peptic ulcers, autoimmune gastritis and stomach and esophageal cancers 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 importance, little is known about the molecular and genetic pathways that direct the generation and maturation of PCs from stem cells.

Looking to gain new insights into the generation of PCs, researchers at Baylor College of Medicine and collaborating institutions have now identified the genes that are preferentially expressed by emerging PCs to guide their development. Their studies, involving mouse models and human gastric cells, discovered a “training program” driving PC development from stem cells and subsequent maturation into active acid-secreting cells. This was dependent on expression of an orphan nuclear receptor, ERRγ. The findings, they suggest, 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, such as killing bacteria in contaminated food, facilitating food digestion and promoting absorption of minerals including phosphate, calcium, and iron. But acid can also be dangerous, causing conditions from reflux to peptic ulcers to gastric bleeds that can be life-threatening,” said corresponding author Jason Mills, MD, PhD, Herman Brown Endowed Professor of medicine—gastroenterology and co-director of the Texas Medical Center Digestive Disease Center (DDC) at Baylor.

Mills and colleagues reported on their studies in Cell Stem Cell, in a paper titled “Metabolic regulatory ERRγ governs gastric stem cell differentiation into acid-secreting parietal cells,” in which they reported, ”ERRγ emerged as the transcription factor governing emergence of PC progenitors from stem cells.”

Parietal cells produce gastric acid to kill pathogens and aid digestion, and dysregulated PC census is common in diseases ranging from common disorders such as indigestion and heartburn, to more chronic conditions, including peptic ulcer disease, autoimmune gastritis and gastroesophageal reflux, to malignant diseases, such as gastric and esophageal cancers. However, the team continued, “… we know shockingly little about how these complex metabolic powerhouses arise from gastric epithelial stem cells.”

Studying how these cells are generated can help scientists understand disorders relating to parietal cell dysfunction. These may include disorders linked to the stomach stopping PC production, which creates an acid-free stomach that promotes gastric cancer, or, conversely,  disorders in which the stomach makes too many PCs and too much acid.

Estrogen-related receptors (ERRs) are a family of orphan nuclear receptors (ERRα, ERRβ, and ERRγ) that respond to and regulate cellular metabolic states, the authors further noted. Interestingly, they noted, “ERRγ expression is largely confined to highly metabolic tissues. In embryonic stomach ERRγ is required for induction of PC genes, and its expression is lost during gastric cancer.”

For their reported study the researchers set up a genetic PC ablation model that let them track the stages of PC regeneration from stem cells using morphological, ultrastructural, and single-cell RNA sequencing (scRNA-seq) analyses.

“Our first step was to generate enough PCs to study their development and maturation,” said co-first author of the study, Mahliyah Adkins-Threats, PhD, who was a graduate student in the Mills lab while working on this project. “PCs are long-lived (about two months), so we needed a system that would allow us to characterize the PC differentiation process in a shorter time.”

The researchers worked with a mouse model in which they eliminated existing PCs. “This triggered the production of new cells in which we were able to capture a first glimpse into 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 the team identified what genes the cells were turning on or off as they became more mature PCs. They discovered that of all the genes expressed by the cells, there was one, estrogen-related receptor gamma (ERRγ), a gene involved in regulating cell metabolism, that was expressed in both very young parietal cells and in fully functional parietal cells. ERRγ 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, a member of 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 these acid secreting PCs.”

“Importantly, when we deleted the Esrrg gene in the gastric epithelium, whole gastric sections completely lacked any PC lineage cells, indicating that this gene is not only sufficient but also required for stem cells to commit to the PC lineage,” Adkins-Threats said. “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.”

In their paper the authors said their results suggest that ERRγ may have evolved a specific role in the stomach, inducing metabolic genes essential for PC maturation and enforcing PC cell fate in stem-cell-derived cells. “The sole reliance on a single gene (Esrrg) for PC specification and maturation is unexpected, though an earlier study of global Esrrg null mice did hint that it was important for embryonic emergence of PCs,” they commented. “Unlike other characterized PC-specific genes, deletion of Esrrg leads to the absence of PCs from birth onward.”

Noting limitations of their study, the researchers concluded, “Overall, our results highlight how a druggable, metabolically regulated, metabolism-regulating transcription factor is required for stem cell commitment to and maturation of PCs … ERRγ is affected by xenobiotics and can be drugged. Thus, the results suggest previously unappreciated ways in which differentiation and cellular metabolism can be coordinated as well as potential methods for intervening in the cellular census of functional cells involved in many disease processes.”

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