Gastroenterology
Volume 138, Issue 2 , Pages 426-429, February 2010

Sonic Hedgehog: A Link Between Inflammation, Gastric Atrophy, and Acid Suppression?

  • Willemijn A. Van Dop

      Affiliations

    • Center for Experimental Molecular Medicine and Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands
    • ,
  • Gijs R. Van Den Brink

      Affiliations

    • Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands
    • Corresponding Author InformationReprint requests Address requests for reprints to: Gijs R. van den Brink, Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands

published online 23 December 2009.

Article Outline

 

See “Loss of parietal cell expression of Sonic Hedgehog induces hypergastrinemia and hyperproliferation of surface mucous cells,” by Xiao C, Ogle SA, Schumacher MA, et al, on page 550; and “Interleukin-1β promotes gastric atrophy through suppression of Sonic Hedgehog,” by Waghray M, Zavros Y, Saqui–Salces M, et al, on page 562.

The morphogen Sonic hedgehog (Shh) was shown to be expressed in gastric glands several years ago,1, 2 but the physiological significance of Shh signaling in the stomach awaited careful analysis. Two studies in this month's issue of Gastroenterology considerably advance our understanding of the regulation and function of Shh signaling in the mouse stomach.

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Gastric Epithelial Patterning 

Tubular epithelial structures, which are often referred to as units, invaginate into the gastric mucosa and contain a zone of proliferating cells in the isthmus somewhere halfway between the base of the unit and the mucosal surface. From the isthmus, there is bidirectional migration of cells. Cells that migrate toward the mucosa surface form the pit or foveolar region. Cells that migrate to the base of the gastric units form the gland proper, which has a neck region just below the isthmus and a base. In the distal antral region, units have a large foveolar region and a relatively small and coiled glandular region that contains mucous cells and a large number of endocrine cells, such as gastrin-producing G cells and somatostatin-producing D cells. The proximal stomach contains fundic glands, which contain parietal cells, mucous neck cells (located in the neck) that transdifferentiate into zymogenic cells as they migrate to the gland base, and endocrine cells, such as D cells and histamine-secreting ECL cells.

Transforming growth factor-α is a foveolar cell fate promoting factor. Overexpression of transforming growth factor-α is responsible for the massively enlarged foveolar compartment in Ménétrier disease.3, 4 Wnt signaling positively regulates the size of the glandular region because Wnt pathway activating mutations cause fundic gland polyps that are characterized by specific expansion of this compartment.5, 6 We have shown previously that Shh is expressed in the parietal cells of humans and several gland cell lineages in rodents and suggested that Shh may be a gland cell-type promoting factor.1, 2

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Atrophic Gastritis 

Chronic gastric inflammation such as in Helicobacter pylori infection can lead to thinning of the mucosa with loss of gastric units and progressive loss of glandular cell types and development of metaplasia, so called atrophic gastritis. Atrophic gastritis is characterized by pronounced loss of gastric acidity (hypochlorhydria). The clinical relevance of atrophic gastritis lies in the fact that it is the precursor to the development of epithelial dysplasia and “intestinal type” gastric cancer, the most frequently occurring type of gastric cancer.

A study by Gordon et al7 suggested that loss of parietal cell function may play a central role in the development of gastric atrophy. The authors generated a mouse model in which the parietal cells were specifically ablated. In their experiments, it was shown that loss of parietal cells resulted in subsequent loss of mucous neck cells and zymogenic cells, whereas the foveolar compartment was expanded. These data suggest that the parietal cells secrete a factor that regulates the cell fate of the other gastric cell lineages and that loss of expression of such a factor may play a role in the development of atrophic gastritis. This parietal cell–derived factor may well be hydrochloric acid because loss of gastric acidity results in hypergastrinemia and chronic hypergastrinemia results in progressive foveolar hyperplasia and glandular atrophy in mice, similar to parietal cell–depleted mice.8

It was shown previously that loss of Shh expression correlated with the degree of gastric atrophy and intestinal metaplasia in H pylori–infected patients and Mongolian gerbils.9, 10 This suggested the possibility that Shh is a parietal cell–derived factor that may act in parallel with or up- or downstream of hydrochloric acid in affecting the other gastric cell lineages. Zavros et al11 have shown convincingly that gastric Shh expression and hedgehog signaling depend on circulating gastrin serum levels and gastric acidity. However, although we have some insight into the regulation of gastric Shh expression, so far we have little information on the functional role of Shh signaling in the stomach.

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New Insights Into the Role of Shh 

Two studies in this issue of Gastroenterology now use reliable tools to advance our understanding considerably of Shh's role in the stomach. Waghray et al. carefully map Shh expression in the normal mouse stomach and find that Shh is broadly expressed by the epithelial cell lineages of the gastric gland as described previously.1 In addition, foveolar cells seem also to express Shh to some degree at least at the mRNA level, a finding that concurs with a previous description of positive foveolar cells in the antrum of the Shh-LacZ mouse by Kolterud et al.12 The authors go on to show that Shh expression is progressively lost upon infection with H. felis similar to humans and Mongolian gerbils. Importantly, however they show for the first time that loss of Shh expression is not merely the result of loss of gland cell types but actually precedes it. This is an important step in examining any possible causality between loss of Shh expression and development of glandular atrophy. In this study, Shh mRNA expression is significantly repressed by Interleukin-1β (Il-1β), one of the key cytokines with a role in H pylori associated gastric cancer development.13 The authors show further that Shh mRNA expression is significantly reduced by omeprazole, and thus, seems to depend upon gastric acidity. Suppressive effects of Il-1β on gastric acidity have been well documented14, 15 and loss of Shh in response to Il-1β may therefore in part be indirect. However, Waghray et al16 show that effects of interleukin-1β and omeprazole are additive suggesting that they are mediated at least in part by parallel pathways.

Xiao et al17 generate a parietal cell–specific knockout of Shh (HKCre-ShhKO) to examine the functional role of Shh signaling in vivo. Because Shh may be more broadly expressed by the different cell lineages of the gastric epithelium and the authors show complete loss of Shh mRNA expression in the neck region of the gastric units but not in total glands, it is not entirely clear whether some degree of Shh expression and signaling may remain. Two phenotypic changes are observed in the HKCre-ShhKO that are remarkably similar to both the parietal cell depleted and hypergastrinemic mice mentioned.7, 8 The most notable change is an expansion of the foveolar compartment, which was more modest in the parietal cell depleted mice, but these mice were examined at little more than 1 month of age and Xiao et al17 show that their phenotype also increases with age. The second phenotypic change observed in both models is the diminished differentiation of the mucous neck and zymogenic cell lineage. Xiao et al17 demonstrate that histamine-stimulated acid secretion is severely compromised in HKCre-ShhKO mice. This explains why the mice develop significant hypergastrinemia and seems to have raised the question to what extent the hypergastrinemia was responsible for the observed phenotype. It is subsequently elegantly shown that the molecular and morphological changes in the HKCre-ShhKO can be entirely reversed by treatment with octreotide, a somatostatin analog that inhibits the secretion of gastrin and other hormones. Thus, although some of the effects of loss of Shh on gastric epithelial morphology may be direct, it seems that the changes are to a large degree indirect and the result of hypergastrinemia. The HKCre-ShhKO did not show diminished parietal cell numbers even at 8 months of age. Assuming that Shh expression was completely lost in the HKCre-ShhKO mice, this suggests that although loss of Shh may precede loss of parietal cells in the development of atrophic gastritis it is unlikely that loss of Shh is responsible for the loss of parietal cells. However, loss of Shh may be involved in the development of hypochlorhydria and resulting hypergastrinemia.

An intriguing matter that remains is how loss of Shh expression leads to such pronounced loss of sensitivity to histamine regulated acid secretion? One of the important questions directly related to this issue is if parietal cells are direct targets of hedgehog signaling or if effects are mediated indirectly via the mesenchyme. We reported initially that epithelial cells in the stomach and intestine express the hedgehog receptor Patched (Ptch),1 but these results were based on antibodies that turned out to give nonspecific staining. We later found that at least in the intestine Ptch expression is restricted to the mesenchyme.18 Indeed, careful characterization of hedgehog target cells in the gut using a variety of reporter mice12 has shown that signaling is exclusively from the epithelium to the mesenchyme in the colon, small intestine, and antral region of the stomach, but the fundic glands were not described. Additionally, Stepan et al19 have shown data that suggest that isolated parietal cells may respond directly to hedgehog signaling. Perhaps parietal cells are an exception to the rule that signaling is exclusively paracrine in the gastrointestinal tract? Xiao et al17 observed disorganization of the secretory membrane in the parietal cells of HKCre-ShhKO mice, so is Shh directly or indirectly (via a secondary signal from the mesenchyme) required for full differentiation and functionality of the parietal cell to occur?

In conclusion, parietal cells secrete factors that directly or indirectly affect differentiation of the other gastric cell lineages and are lost in atrophic gastritis. Both hydrochloric acid and Shh seem to be such factors and it now seems that their regulation is intimately linked. The picture that is emerging from the 2 publications in this issue of Gastroenterology is that loss of Shh results in a primary defect in parietal cell function which results in hypochlorhydria. The subsequent development of hypergastrinemia seems to be responsible for many of the morphologic alterations that are observed. It will be interesting to see what the mechanism is behind the apparent regulation of parietal cell differentiation and function by Shh. Does autocrine Shh signaling occur in parietal cells or is signaling paracrine? Also, because both Wnt and Shh signaling seem to affect the glandular compartment, what is their precise relationship? The availability of a variety of conditional alleles for components of the hedgehog pathway will undoubtedly further advance our understanding of the role of hedgehog signaling in the stomach in the coming years and may teach us valuable lessons about the molecular mechanisms underlying the development of gastric atrophy (Figure 1).

  • View full-size image.
  • Figure 1. 

    A model of the intimate link between Shh and acid secretion. H+ secretion is required for expression and processing of Shh. Autocrine or paracrine signaling by Shh is in turn required for full functional differentiation and acid secretion of the parietal cell. Loss of Shh results in loss of acidity, diminished production of somatostatin, and a resulting raise in serum gastrin levels. Interleukin-1β has known negative effects on acid secretion and positive effects in gastrin secretion, but is now shown to also down-regulate Shh which may contribute to the loss of the parietal cells capacity to secrete hydrochloric acid.

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References 

  1. Van Den Brink GR, Hardwick JC, Tytgat GN, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology. 2001;121:317–328
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 Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(09)02155-6

doi:10.1053/j.gastro.2009.12.013

Refers to article:

  • Editorial Accompanies ArticleAdditional Online Content Available Loss of Parietal Cell Expression of Sonic Hedgehog Induces Hypergastrinemia and Hyperproliferation of Surface Mucous Cells , 11 November 2009

    Chang Xiao, Sally A. Ogle, Michael A. Schumacher, Melissa A. Orr–Asman, Marian L. Miller, Nantaporn Lertkowit, Andrea Varro, Frederic Hollande, Yana Zavros
    Gastroenterology February 2010 (Vol. 138, Issue 2, Pages 550-561.e8)

  • Additional Online Content AvailableEditorial Accompanies Article Interleukin-1β Promotes Gastric Atrophy Through Suppression of Sonic Hedgehog , 02 November 2009

    Meghna Waghray, Yana Zavros, Milena Saqui–Salces, Mohamad El–Zaatari, C. Bharath Alamelumangapuram, Andrea Todisco, Kathryn A. Eaton, Juanita L. Merchant
    Gastroenterology February 2010 (Vol. 138, Issue 2, Pages 562-572.e2)

Gastroenterology
Volume 138, Issue 2 , Pages 426-429, February 2010

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