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

Abstract

<i>Helicobacter pylori</i>-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 <i>cag</i> 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 <i>H. pylori</i>-infected gastric mucosa. Lineage tracing was induced in <i>Lrig1-CreERT2/+;R26R-YFP/+</i> (Lrig1/YFP) mice that were uninfected or subsequently infected with <i>cag</i>⁺<i>H. pylori</i> or an isogenic <i>cagE</i>^<i>-</i> mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) <i>H. pylori</i> 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 <i>cagE</i>^- mutant. WT <i>H. pylori</i>-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 <i>H. pylori</i> In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic <i>H. pylori</i> infection stimulates Lrig1-expressing progenitor cells in a <i>cag</i>-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.