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Molecular ‘switch’ may illuminate stomach disorders

May. 19, 2022, 9:25 AM


by Bill Snyder

An international team that included researchers from Vanderbilt University Medical Center has discovered a molecular switch that induces rapid proliferation of zymogen granule-secreting chief cells in the stomach to regenerate damaged tissue.

The finding, which was reported earlier this month in the journal Cell Stem Cell, may be crucial to understanding gastric pathologies, including certain chronic, premalignant conditions.

A population of adult gastric cells in the stomach called “chief cells” normally secrete granules containing precursors, or zymogens, of digestive enzymes and do not proliferate. When tissue damage occurs, however, they can suddenly switch to a rapidly proliferating, regenerative function.

Eunyoung Choi, PhD

To better understand this, researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VUMC and Pohang University of Science and Technology in the Republic of Korea (South Korea) utilized a novel mouse model to trace the effects of stomach tissue injury at a single-cell level.

The transgenic mouse model was generated in the laboratory of Eunyoung Choi, PhD, assistant professor of Surgery and a faculty member of the Epithelial Biology Center at VUMC, and one of three corresponding authors of the paper.

The modelallows us to track cell fate changes of cells of origin in metaplasia and gastric cancer and is a unique model in the gastric cancer field,” Choi said.

By characterizing transcribed genes using a technique called transcriptome analysis, they confirmed that, when tissue injury occurs, the level of a protein called p57 rapidly decreases in chief cells and is followed by rapid proliferation.

When p57 was overexpressed in stomach organoids, three-dimensional cell cultures derived from stem cells, the cells behaved more like mature, secretary stem cells that do not proliferate. Reducing p57 expression induced proliferation.

The findings demonstrate that p57 is a gatekeeper that keeps stomach chief cells in a reserve, non-proliferative stem cell state. This information may be important in understanding pre-malignant stomach conditions such as spasmolytic polypeptide-expression metaplasia (SPEM).

Jimin Min, PhD, a postdoctoral fellow in Choi’s lab, and Brianna Caldwell, MBA, research assistant III, were co-authors of the study.

VUMC’s contributions to the study were supported by awards from the U.S. Department of Defense and National Institutes of Health, and by pilot funding from the Vanderbilt Digestive Diseases Research Center and the Vanderbilt-Ingram Cancer Center GI SPORE.

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