Abstract
The stem cell in the isthmus of gastric units continually replenishes the epithelium. Atrophy of acid-secreting parietal cells (PCs) frequently occurs during infection with Helicobacter pylori, predisposing patients to cancer. Atrophy causes increased proliferation of stem cells, yet little is known about how this process is regulated. Here we show that CD44 labels a population of small, undifferentiated cells in the gastric unit isthmus where stem cells are known to reside. Loss of CD44 in vivo results in decreased proliferation of the gastric epithelium. When we induce PC atrophy by Helicobacter infection or tamoxifen treatment, this CD44(+) population expands from the isthmus toward the base of the unit. CD44 blockade during PC atrophy abrogates the expansion. We find that CD44 binds STAT3, and inhibition of either CD44 or STAT3 signaling causes decreased proliferation. Atrophy-induced CD44 expansion depends on pERK, which labels isthmal cells in mice and humans. Our studies delineate an in vivo signaling pathway, ERK → CD44 → STAT3, that regulates normal and atrophy-induced gastric stem/progenitor-cell proliferation. We further show that we can intervene pharmacologically at each signaling step in vivo to modulate proliferation.
Highlights
Gastric parietal cell atrophy causes metaplasia, reactive stem cell proliferation, and increased risk for cancer
CD44 is highly expressed in gastric cancer cell lines [32], H. pylori-infected human patient epithelia [32, 33], gastric carcinomas [34, 35], intestinal metaplasia [35, 36], and dysplasia [37]
CD44 is expressed in gastric tumors [32, 33, 38], its expression has not been characterized in normal mouse corpus gastric epithelial tissue [39], but it has been observed in the antral epithelium [32] and at the squamous-corpus junction [40]
Summary
Gastric parietal cell atrophy causes metaplasia, reactive stem cell proliferation, and increased risk for cancer. Our studies delineate an in vivo signaling pathway, ERK 3 CD44 3 STAT3, that regulates normal and atrophyinduced gastric stem/progenitor-cell proliferation. PC atrophy causes increased proliferation of normal stem/progenitor cells in the isthmus [6, 7]. A handful of molecular pathways and markers [23,24,25] have been proposed for the gastric epithelium, but no mechanistic studies revealing molecules that regulate proliferation of the canonical isthmal stem cell either under normal conditions or in response to injury have been reported [4]. Our results identify for the first time an in vivo signaling pathway that mediates the response of the normal stem/progenitor cell compartment to a metaplasia-inducing injury
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