Indian Hedgehog mediates gastrin-induced proliferation in stomach of adult mice

Gastroenterology. 2014 Sep;147(3):655-666.e9. doi: 10.1053/j.gastro.2014.05.006. Epub 2014 May 20.


Background & aims: Loss of expression of Sonic Hedgehog (Shh) from parietal cells results in hypergastrinemia in mice, accompanied by increased expression of Indian Hedgehog (Ihh) and hyperproliferation of surface mucous cells. We investigated whether hypergastrinemia induces gastric epithelial proliferation by activating Ihh signaling in mice.

Methods: We studied mice with parietal cell-specific deletion of Shh (PC-Shh(KO)) and hypergastrinemia, crossed with gastrin-deficient (GKO) mice (PC-Shh(KO)/GKO). When mice were 3-4 months old, gastric tissues were collected and analyzed by histology, for incorporation of bromodeoxyuridine, and for expression of the surface mucous cell marker Ulex europaeus. PC-Shh(KO)/GKO mice were given gastrin infusions for 7 days; gastric surface epithelium was collected and expression of Ihh was quantified by laser capture microdissection followed by quantitative reverse transcriptase polymerase chain reaction. Mouse stomach-derived organoids were incubated with or without inhibitors of WNT (DKK1) or Smoothened (vismodegib) and then cocultured with immortalized stomach mesenchymal cells, to assess proliferative responses to gastrin.

Results: Gastric tissues from PC-Shh(KO)/GKO mice with hypergastrinemia had an expanded surface pit epithelium, indicated by a significant increase in numbers of bromodeoxyuridine- and Ulex europaeus-positive cells, but there was no evidence for hyperproliferation. Gastrin infusion of PC PC-Shh(KO)/GKO mice increased expression of Ihh and proliferation within the surface epithelium compared with mice given infusions of saline. In gastric organoids cocultured with immortalized stomach mesenchymal cells, antagonists of WNT and Smoothened inhibited gastrin-induced proliferation and WNT activity. Activity of WNT in media collected from immortalized stomach mesenchymal cells correlated with increased expression of glioma-associated oncogene homolog 1, and was inhibited by DKK1 or vismodegib.

Conclusions: Ihh signaling mediates gastrin-induced proliferation of epithelial cells in stomachs of adult mice.

Keywords: Development; Gastric Epithelium; Signal Transduction; Tissue Regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation*
  • Coculture Techniques
  • Disease Models, Animal
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gastric Mucosa / metabolism*
  • Gastric Mucosa / pathology
  • Gastrins / administration & dosage
  • Gastrins / deficiency
  • Gastrins / genetics
  • Gastrins / metabolism*
  • Hedgehog Proteins / deficiency
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Infusions, Parenteral
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organoids
  • Receptors, G-Protein-Coupled / metabolism
  • Smoothened Receptor
  • Stomach Diseases / genetics
  • Stomach Diseases / metabolism*
  • Stomach Diseases / pathology
  • Time Factors
  • Wnt Signaling Pathway
  • Zinc Finger Protein GLI1


  • Dkk1 protein, mouse
  • Gastrins
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Intercellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors
  • Receptors, G-Protein-Coupled
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein GLI1
  • ihh protein, mouse