The presumptive gastric corpus stem cell population is CD44‐positive and expands during metaplasia via increased ERK‐MAPK signaling

Abstract

Little is known about the epithelial stem cell (SC) of the gastric corpus, though most gastric cancers arise in the setting of altered SC biology. We have established that injection of the drug tamoxifen, leads to complete atrophy of parietal cells (PCs) by 3 days. That injury causes metaplastic gastric differentiation, characterized by an expanded, undifferentiated population within the normal SC niche in the isthmus. Here we show that CD44 labels undifferentiated, Ki67+ isthmal cells in normal epithelium that expand ≥fourfold upon tamoxifen injury. Also, untreated CD44−/− mice have reduced basal rates of proliferation. Hence, we sought to determine signaling pathways that regulate the injury induced expansion of CD44+ stem/progenitor cells. Tamoxifen causes a burst of ERK phosphorylation in the stomach within 6 hours, when PCs first begin to die. Nuclear pERK labels the expanding isthmal cells. Inhibiting pERK with U0126 blocks expansion. Stat3, which marks SC proliferation, is also highly expressed and activated by phosphorylation following tamoxifen injury. We find that CD44 binds to Stat3 to regulate cell‐cycle genes (CyclinD1) during CD44+ cell expansion. Thus, our data suggest that CD44 marks undifferentiated epithelial cells within the SC niche of the gastric unit, greatly expands on injury and is regulated by ERK. CD44 enhances SC proliferation by associating with Stat3. Our study is the first one to identify signaling pathways and molecular markers specific for regulating the presumptive SC of the corpus epithelium during homeostasis.