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Defining the origin of gastric metaplastic cells

A schematic of metaplasia arising from the chief cells in a stomach corpus gland. Proliferating cells are shown in gray, chief cells in green (GFP-labeled in the study), and SPEM (metaplastic) cells are shown as larger green cells. From the left, the graphic shows the makeup of a normal gland, a gland after the initial transdifferentiation of chief cells into metaplastic cells, and finally a metaplastic gland. Note that metaplastic cells are called “SPEM cells” in this graphic.


By Wendy Bindeman

Eunyoung Choi, assistant professor of surgery, and first author Brianna Caldwell, a research assistant in the Choi lab, have identified the origin of metaplasia in the stomach. Metaplasia is a key initiating step in the development of gastric cancer, and which cell type gives rise to it has been a subject of significant debate. Their latest paper was published on September 8, 2021, in the journal Gut.

We sat down with Eunyoung Choi to learn more about this exciting new research.

What problem does your research address?

Headshot of Dr. Eunyoung Choi wearing a pleated cream blouse and a necklace with matching earrings.
Eunyoung Choi, assistant professor of surgery.

Metaplasia—the conversion of one mature cell type into another—commonly occurs in response to injury in many types of mucus membranes, and metaplastic cells are considered to be precursor cells for many cancers. Our lab focuses on gastric cancer, which originates from metaplastic cells in the mucus membrane of the stomach. Although identification of the cell-of-origin of metaplasia is critical to understanding how disease arises after mucosal injury, the distinct roles of different types of epithelial cells during the development of metaplasia have not been completely defined. Specifically, there is considerable debate about whether metaplasia in the stomach originates with isthmal progenitor cells or chief cells—two types of cells common in the stomach.

Headshot of Brianna Caldwell. She is wearing a collared denim shirt and her hair down to her shoulders.
First author Brianna Caldwell.

Over the past decade, many groups have reported that stomach metaplasia originates from chief cells, which are gastric epithelial cells found in the base of stomach glands called corpus glands. However, recent publications have suggested that isthmal progenitor cells, which are responsible for homeostasis in normal gastric cell lineages, are responsible for metaplasia. These conflicting results require more definitive analyses using representative model systems to determine the true origin of stomach metaplasia.

What was unique about your approach to the research?

We used a mouse model of acute stomach injury and a novel, long-lasting labeling strategy that specifically targeted chief cells.

What were your findings?

Our study provides definitive evidence of two distinct roles of chief cells and isthmal progenitor cells during development of metaplasia: the chief cells directly give rise to metaplastic cells through transdifferentiation (re-differentiation of a mature cell into a different cell type), while the isthmal progenitor cells contribute to the expansion of foveolar cells (mucus-secreting cells).

We have also defined a new role of chief cells as a potential source of expanded surface cell lineages during the development of metaplasia.

Where is this research taking you next? What will you personally be doing, or how will other researchers build on this work?

We plan to investigate the mechanisms that control the conversion of metaplastic cell lineages (originating originate from chief cells during metaplastic progression and evolution) to dysplasia (benign, abnormal cells) and cancer. Later on, additional studies using chronic injury models such as Helicobacter felis or Helicobacter pylori infections or oncogenic gene activation would further clarify the roles of chief cell plasticity during the entire process of gastric carcinogenesis.

What are the societal/environmental/economic benefits of this research?

Gastric cancer is one of the largest causes of cancer-related deaths worldwide; the incidence of early-onset gastric cancer, particularly in women, is steadily increasing in the United States and Latin America. Our paper contributes to our understanding of gastric cancer development and resolves a conflicting paradigm in the field about the origin of metaplastic cells in the stomach. Better understanding of the early stages of disease can contribute to improved prevention, diagnosis, and treatment.


These studies were supported by grants from the Department of Defense (Choi), the NIH (Choi, Meyer, Engevik, Weis), and pilot funding from VICC (Choi).

Go deeper

The paper “Chief cell plasticity is the origin of metaplasia following acute injury in the stomach mucosa“ was published in the journal Gut on September 8, 2021.