Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA132

Poster Communications

Epithelial regeneration after gastric ulceration causes prolonged altered cell types and weakened defenses in mice

E. Aihara1, A. Matthis1, K. Engevik1, M. Montrose1

1. Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States.


The peptic ulcer heals through a complex process, although the ulcer relapse often occurs several years later after healing even in H. pylori eradicated or non-NSAIDs treated patients. Our hypothesis is that even after visual evidence of healing of gastric ulceration, the regenerated epithelium is aberrant for an extended interval, increasing susceptibility of the regenerated epithelium to damage and further diseases. C57BL/6J (Wilde-type), TFF2 KO and NHE2 KO mice were used in the present study. Under isoflurane anesthesia, the abdomen was incised and the intact stomach exposed. A microcapillary tube (0.7 mm in diameter) filled with acetic acid (99%) was placed in contact with the exterior surface of the stomach corpus region and left in place for 25 s. A single gavage of 106 H. pylori (Sydney strain 1) was performed 30 days after ulcer induction. Gastric corpus ulcers induced by acetic acid visually healed in a time dependent manner, and they cannot be identified macroscopically at 30 days after ulceration. However, Day 30 regenerated epithelial architecture was poor. The gene profile of regenerated tissue was abnormal, indicating increased stem/progenitor cells, deficient differentiated gastric cell types, and deranged cell homeostasis. Despite upregulation of PDX1 in the regenerated epithelium, no mature antral cell type, such as gastrin-expressing cell, was observed. Using RT-PCR or immunostaining, the regenerated epithelium at 30 days and 4 months is shown to completely lack parietal cells (H-K ATPase) and Na/H exchanger 2 (NHE2: a TFF2 effector in gastric healing) while the trefoil factor 2 (TFF2) co-expressed GSII (Griffonia Simplicifolia lectin II), DCLK1 (Tuft cell marker: doublecortin like kinase), SOX9, or Ki67 are upregulated and widely distributed even deep in the gastric gland, suggesting that regenerated epithelium sustains a metaplastic condition. Similar to ulcer-regenerated epithelium in the wild-type mouse stomach, gastric epithelium in NHE2 KO lacked parietal cells and upregulated TFF2/GSII and DCLK1, SOX9, and Ki67 in the base of gland, suggesting that NHE2 plays important roles in maturation of gastric epithelium. Gastric ulcer healing was strongly delayed in TFF2 knockout mice, and re-epithelialization was accompanied with upregulation of GSII. Following H. pylori inoculum 30 days after ulceration, we observed that the gastric ulcer selectively relapses at the same site where it was originally induced, although H. pylori did not cause gastric injury in other sites. Follow up at 8 months showed that the relapsed ulcer was not healed in H. pylori infected tissues. These findings reveal that this macroscopically regenerated epithelium has prolonged abnormal cell distribution and is differentially susceptible to subsequent damage by H. pylori.

Where applicable, experiments conform with Society ethical requirements