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 (HKCreERT2;Shhflox/flox or PC-iShhKO) was developed. Stomachs were collected and compared 7 to 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 HKCreERT2 or Shhflox/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 Helicobacter pylori correlates with re-expression of Shh, regeneration of the gastric epithelium and ulcer healing.

Hedgehog signaling in the stomach

“…Interestingly, Ptch was expressed within the mesenchyme, but also co-localized to CD44+/Shh+cells within the tumor (Figure 3). These data are consistent with studies demonstrating that Hedgehog maintains the malignant transformation phenotype in CD44+ gastric cancer cells that promotes chemotherapy resistance [18]. A recent study by Syu et al [42] further supports the role of Hedgehog signaling as a driver in the progression of gastric cancer.…”

“…Shh is a parietal cell-secreted protein regulating gastric cell proliferation, differentiation, function and epithelial regeneration [7,18]. Intriguingly, Shh acts as a chemokine for monocyte recruitment during H. pylori infection and the development of gastritis [32].…”

“…The development of a mouse model expressing a parietal cell-specific deletion of Shh (HKCre/Shh KO mice) has allowed us to assay changes in gastric epithelial cell differentiation, function and regeneration [15-18]. Compared to pathology of the control animals, HKCre/Shh KO mice demonstrated an age-dependent increase in number of surface pit mucous cells reminiscent of foveolar hyperplasia [15].…”

“…This suggested for the first time that parietal cell act as an endocrine source of Shh during gastric repair. In addition, the development of a tamoxifen-inducible mouse model expressing a parietal cell-specific deletion of Shh (PC-iShhKO) demonstrated that re-emergence of Shh contributes to gastric regeneration [18]. Studies have indicated that downregulating Shh expression is a mechanism by which Helicobacter pylori (H. pylori) infection triggers gastric cancer, as the outcome of H. pylori infection is parietal cell atrophy and gastric hypochlorhydria.…”

“…Decreases in the expression of Shh and Ptch1 have been observed in parietal cells during H. pylori infection of the gastric epithelium [34]. These finding represents changes during the early stages of H. pylori infection that takes place in gastric mucosal cells prior to neoplastic transformation [18]. …”