title: Sonic Hedgehog contributes to gastric mucosal restitution after injury.
abstract: Eradication of Helicobacter pylori correlates with regeneration of the gastric epithelium, ulcer healing and re-expression of the gastric morphogen Sonic Hedgehog (Shh). We sought to identify the role of Shh as a regulator of gastric epithelial regeneration during wound healing. A mouse model expressing a parietal cell-specific, tamoxifen-inducible deletion of Shh (HKCre(ERT2);Shh(flox/flox) or PC-iShhKO) was developed. Stomachs were collected and compared 7-150 days after the final vehicle or tamoxifen injection. Ulcers were induced in both controls and PC-iShhKO mice using acetic acid and ulcer size compared 1 and 7 days post induction. (1) Re-expression of Shh correlates with decreased hyperproliferation: Compared to controls, PC-iShhKO mice developed foveolar hyperplasia. Restoration of normal gastric epithelial architecture and differentiation correlated with the re-expression of Shh in PC-iShhKO mice 150 days after the final tamoxifen injection. At the tamoxifen dose used to induce Cre recombination there was no genotoxicity reported in either HKCre(ERT2) or Shh(flox/flox) control mouse stomachs. (2) Delayed wound healing in PC-iShhKO mouse stomachs: To identify the role of Shh in gastric regeneration, an acetic acid ulcer was induced in control and PC-iShhKO mice. Ulcers began to heal in control mice by 7 days after induction. Ulcer healing was documented by decreased ulcer size, angiogenesis, macrophage infiltration and formation of granulation tissue that correlated with the re-expression of Shh within the ulcerated tissue. PC-iShhKO mice did not show evidence of ulcer healing. Re-expression of Shh contributes to gastric regeneration. Our current study may have clinical implications given that eradication of H. pylori correlates with re-expression of Shh, regeneration of the gastric epithelium and ulcer healing.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Xiao
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.forename: Amy C
authors.initials: AC
authors.lastname: Engevik
authors.forename: Jason R
authors.initials: JR
authors.lastname: Martin
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tritschler
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.forename: Robert
authors.initials: R
authors.lastname: Koncar
authors.forename: Joseph
authors.initials: J
authors.lastname: Roland
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
authors.forename: Yana
authors.initials: Y
authors.lastname: Zavros
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005753:Gastric Mucosa / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013276:Stomach Ulcer / Q000378:metabolism*; D013629:Tamoxifen; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
chemical_list: D002352:Carrier Proteins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C498447:Hhip protein, mouse; D051741:Kruppel-Like Transcription Factors; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; C465570:Shh protein, mouse; D042461:Vascular Endothelial Growth Factor A; D000071676:Zinc Finger Protein GLI1; C467480:vascular endothelial growth factor A, mouse; D013629:Tamoxifen