The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation

J Biol Chem. 2013 May 31;288(22):16085-97. doi: 10.1074/jbc.M112.445551. Epub 2013 Apr 15.

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.

Keywords: Cd44; ERK; Gastric Cancer; Hyaluronan; PEP-1; Signaling; Stem Cells; Tamoxifen; U0126; WP1066.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Female
  • Helicobacter Infections / genetics
  • Helicobacter Infections / metabolism*
  • Helicobacter Infections / pathology
  • Helicobacter pylori / metabolism*
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • MAP Kinase Signaling System / genetics
  • Male
  • Metaplasia / genetics
  • Metaplasia / metabolism
  • Metaplasia / pathology
  • Mice
  • Parietal Cells, Gastric / metabolism*
  • Parietal Cells, Gastric / pathology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Stem Cells / metabolism*
  • Stem Cells / pathology

Substances

  • CD44 protein, human
  • Cd44 protein, mouse
  • Hyaluronan Receptors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse