Targeted mobilization of Lrig1 + gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system

Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19652-19658. doi: 10.1073/pnas.1903798116. Epub 2019 Sep 5.

Abstract

Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE- mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE- mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.

Keywords: Helicobacter pylori; Lrig1; gastric; progenitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / microbiology
  • Animals
  • Carcinogenesis / pathology
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Female
  • Gastric Mucosa / metabolism
  • Gastritis / metabolism
  • Gastritis / pathology
  • Helicobacter Infections / metabolism
  • Helicobacter Infections / microbiology
  • Helicobacter Infections / pathology
  • Helicobacter pylori / metabolism*
  • Humans
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / microbiology
  • Precancerous Conditions / pathology
  • Primary Cell Culture
  • Risk Factors
  • Stem Cells / metabolism
  • Stomach / microbiology
  • Stomach / pathology
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / microbiology
  • Stomach Neoplasms / pathology
  • Type IV Secretion Systems / metabolism*

Substances

  • LRIG1 protein, human
  • Lrig1 protein, mouse
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Type IV Secretion Systems