title: Epithelial Regeneration After Gastric Ulceration Causes Prolonged Cell-Type Alterations.
abstract: OBJECTIVE
  The peptic ulcer heals through a complex process, although the ulcer relapse often occurs several years later after healing. 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.
  
  
  METHODS
  Gastric ulcers were induced in mice by serosal topical application of acetic acid.
  
  
  RESULTS
  Gastric ulcers induced by acetic acid visually healed within 30 days. However, 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 up-regulation of PDX1 in the regenerated epithelium, no mature antral cell type was observed. Four months after healing, the regenerated epithelium lacks parietal cells, trefoil factor 2 (TFF2) and (sex-determining region Y)-box 9 (SOX9) remain up-regulated deep in the gastric gland, and the Na/H exchanger 2 (a TFF2 effector in gastric healing) remains down-regulated. Gastric ulcer healing was strongly delayed in TFF2 knockout mice, and re-epithelialization was accompanied with mucous metaplasia. AfterHelicobacter pyloriinoculum 30 days after ulceration, we observed that the gastric ulcer selectively relapses at the same site where it originally was induced. Follow-up evaluation at 8 months showed that the relapsed ulcer was not healed inH pylori-infected tissues.
  
  
  CONCLUSIONS
  These findings show that this macroscopically regenerated epithelium has prolonged abnormal cell distribution and is differentially susceptible to subsequent damage byH pylori.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Eitaro
authors.initials: E
authors.lastname: Aihara
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Matthis
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Rebekah A
authors.initials: RA
authors.lastname: Karns
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Engevik
authors.affiliation: Monell Chemical Senses Center, Philadelphia, Pennsylvania.
authors.forename: Peihua
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Digestive Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Yacyshyn
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Marshall H
authors.initials: MH
authors.lastname: Montrose
keywords: CXCR4, C-X-C chemokine receptor type 4; DCLK1, doublecortin-like kinase 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GIF, gastric intrinsic factor; GSII, Griffonia simplicifolia lectin II; Gastric Ulcer Healing; H pylori; HK-ATPase, hydrogen potassium exchanger adenosine triphosphatase; KO, knockout; Lgr5, Leucine-rich repeat-containing G protein-coupled receptor5; MUC, Mucin; Metaplasia; NHE2; NHE2, sodium hydrogen exchanger 2; PCR, polymerase chain reaction; PDX1, pancreatic and duodenal homeobox 1; SOX2, (sex-determining region Y)-box 2; SOX9; SPEM, spasmolytic polypeptide-expressing metaplasia; TFF2; TFF2, trefoil factor 2; UEA-1, ulex europaeus; WT, wild type; cDNA, complementary DNA; mRNA, messenger RNA