# Induction and Evolution of Metaplasia in the Stomach

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $513,901

## Abstract

In the stomach, metaplasia arises in the setting of parietal cell loss or oxyntic atrophy. Two types of
metaplasia occur in the human stomach: intestinal metaplasia (the presence of intestinal goblet cell lineages in
the stomach) and Spasmolytic Polypeptide-Expressing Metaplasia or SPEM (the presence of deep antral gland
type mucus cells in the corpus of the stomach). Investigations over the past decade have led to the
recognition that SPEM lineages are substantially derived from transdifferentiation of protein secreting chief
cells into mucus-secreting SPEM lineages. In addition, increasing evidence suggests that SPEM represents a
physiological local repair lineage that is meant to promote local restitution and then be replaced by normal
lineages. Importantly, the induction of SPEM from chief cells is orchestrated by release of IL-13 from ILC2
intrinsic mucosal immune cells. Elimination of ILC2s blocks the development of SPEM following acute parietal
cell loss. In the setting of chronic injury and inflammation, in addition to alterations in the inflammatory cells
within the metaplastic milieu, there is a resculpting of the stromal fibroblasts that likely supports the altered
metaplastic stem cell niche. We have identified the relocalization of telocyte fibroblast populations to the bases
of metaplastic glands following acute oxyntic atrophy in mice. In addition, we have identified four distinct
populations of fibroblast in the normal and diseased human stomach. Together these findings suggest that
intrinsic mucosal inflammatory cells and fibroblasts within the parenchyma of the metaplastic niche may
promote the maintenance of metaplastic cell lineages as well as their progression to more proliferative and
intestinalized pre-neoplastic lineages. We have hypothesized that intrinsic immune cell populations and altered
fibroblasts promote a remodeled tissue milieu that promotes progression towards neoplasia in the stomach.
To evaluate this hypothesis, we will examine two specific aims: First, we will determine how expansion of
ILC2s promotes metaplasia and its progression. Specifically, we will examine the effects of IL-13 and or ILC2-
co-culture with metaplastic gastroids to promote progression of metaplasia. Additionally, we will define the
transcriptional regulation initiated by IL-13 mediated activation of STAT6 that accounts for induction of
metaplasia progression. Second, we will define specific fibroblast populations that promote the development of
an altered pre-neoplastic milieu in the gastric mucosa. We will assess the dynamics of telocyte populations in
the establishment of the metaplastic milieu in mice and evaluate their ability to promote metaplastic
progression in vitro in co-culture. We will further isolate fibroblast sub-populations from regions of normal,
metaplastic, and cancerous human gastric mucosa to define alterations in fibroblast sub-populations that may
promote a pre-neoplastic niche in the metaplastic mucosa. These studie...

## Key facts

- **NIH application ID:** 10852014
- **Project number:** 5R01DK101332-11
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Eunyoung Choi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $513,901
- **Award type:** 5
- **Project period:** 2014-05-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852014

## Citation

> US National Institutes of Health, RePORTER application 10852014, Induction and Evolution of Metaplasia in the Stomach (5R01DK101332-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10852014. Licensed CC0.

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