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.
Bibliographical noteFunding Information:
This work was supported by NIH 1R01DK083402 grant (Y Zavros). The work was also supported in part by the Digestive Health Center Cincinnati Children’s Medical Health Center (DHC: Bench to Bedside Research in Pediatric Digestive Disease) CHTF/SUB DK078392. These studies were supported by grants to JRG from a Department of Veterans Affairs Merit Review Award, NIH RO1 DK071590, and the AGA Funderburg Award in Gastric Biology Related to Cancer. Transgenic Mouse development utilized the facilities of the Vanderbilt Transgenic Mouse Core Facility supported by the Vanderbilt Digestive Disease Research Center (P30 DK58404) and the Vanderbilt-Ingram Cancer Center (CA68485). We would like to acknowledge the assistance of Monica DeLay manager of the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center, supported in part by NIH AR-47363. All flow cytometric data were acquired using equipment maintained by the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center, supported in part by NIH AR-47363. We also acknowledge the assistance of Dr Marsah Wils-Karp and Alyssa Sproles of The Cincinnati Cytokine/Chemokine/Mediator Measurement Core at the Digestive Health Center Cincinnati Children’s Medical Health Center.
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
- Molecular Biology
- Cell Biology