Faculty Opinions recommendation of Loss of parietal cell expression of Sonic hedgehog induces hypergastrinemia and hyperproliferation of surface mucous cells.

Sonic hedgehog (Shh) is not only essential to the development of the gastrointestinal tract, but is also necessary to maintain the characteristic acid-secreting phenotype of the adult stomach. Gastrin is the only hormone capable of stimulating gastric acid and is thus required to maintain functional parietal cells. We have shown previously that gastrin-null mice display gastric atrophy and metaplasia prior to progression to distal, intestinal-type gastric cancer. Because reduced levels of Shh peptide correlate with gastric atrophy, we examined whether gastrin regulates Shh expression in parietal cells. We show here that gastrin stimulates Shh gene expression and acid-dependent processing of the 45-kDa Shh precursor to the 19-kDa secreted peptide in primary parietal cell cultures. This cleavage was blocked by the proton pump inhibitor omeprazole and mediated by the acid-activated protease pepsin A. Pepsin A was also the protease responsible for processing Shh in tissue extracts from human stomach. By contrast, extracts prepared from neoplastic gastric mucosa had reduced levels of pepsin A and did not process Shh. Therefore processing of Shh in the normal stomach is hormonally regulated, acid-dependent, and mediated by the aspartic protease pepsin A. Moreover parietal cell atrophy, a known pre-neoplastic lesion, correlates with loss of Shh processing.

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Parietal cell-Specific SLC26A9 Deletion induces spontaneous Gastric Carcinogenesis in Mice

10.1101/2020.09.28.316398 ◽

2020 ◽

Author(s):

Xuemei Liu ◽

Taolang Li ◽

Dumin Yuan ◽

Brigitte Riederer ◽

Zhiyuan Ma ◽

...

Keyword(s):

Parietal Cell ◽

Epithelial To Mesenchymal Transition ◽

Cell Function ◽

Wnt Signaling Pathway ◽

Gastric Carcinogenesis ◽

Human Gastric Cancer ◽

Mesenchymal Transition ◽

Sequence Of Events ◽

Cell Expression ◽

Cell Phenotypes

AbstractPrevious study showed that Slc26a9 loss impairs parietal cell function and survival. We investigated whether Slc26a9 loss causes spontaneous gastric carcinogenesis in mice and plays a role in the development and progression in human gastric cancer (GC). Gastric histopathology and potential molecular mechanism were explored in Slc26a9 knockout mice and wild-type littermates as well as Slc26a9fl/fl/Atp4b-Cre and Slc26a9fl/fl mice from 8 days to 18 months by histological and immunohistochemical analyses, quantitative PCR, in situ hybridization, and RNA microarray analysis, respectively. We demonstrated that loss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in mice, and clarified the sequence of events leading to malignant transformation, including Slc26a9 deficiency in parietal cells resulted in dysregulated differentiation of stem cells in an inflammatory environment, activated Wnt signaling pathway to induce gastric epithelia cell hyperproliferation and apoptosis inhibition, as well as spontaneous epithelial to mesenchymal transition-induced cancer stem cell phenotypes. Downregulation of SLC26A9 correlated with GC patient’s short survival.Graphical AbstractLoss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in transgenic mice.

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Immunolocalization of anion exchanger AE2 and cation exchanger NHE-1 in distinct adjacent cells of gastric mucosa

AJP Cell Physiology ◽

10.1152/ajpcell.1994.266.2.c559 ◽

1994 ◽

Vol 266 (2) ◽

pp. C559-C568 ◽

Cited By ~ 96

Author(s):

A. Stuart-Tilley ◽

C. Sardet ◽

J. Pouyssegur ◽

M. A. Schwartz ◽

D. Brown ◽

...

Keyword(s):

Gastric Mucosa ◽

Parietal Cell ◽

Anion Exchanger ◽

Cell Types ◽

Parietal Cells ◽

Morphological Evidence ◽

Mucous Cells ◽

Gastric Glands ◽

Basolateral Membranes ◽

Mucous Neck Cells

The gastric mucosa secretes both protons and bicarbonate. The molecular identity of the H(+)-K(+)-ATPase, which mediates acid secretion, has long been known, but the other components of the secretory machinery and their cellular disposition are less well characterized. This study identifies and localizes in rat and rabbit gastric mucosa a chloride-bicarbonate exchanger protein and a Na(+)-H+ exchanger protein. The previously described band 3-related protein of the parietal cell has been identified by isoform-specific antibodies as anion exchanger (AE) 2 and localized to the basolateral membranes of the parietal cells. The Na(+)-H+ exchanger protein NHE-1 was located in the basolateral membranes of the mucous neck cells, interdigitated between the parietal cells of the gastric glands and in the basolateral membranes of the surface mucous cells. Neither transporter protein was abundantly expressed deep in the gland, where most of the pepsinogen cells reside. Carbonic anhydrase II (CA II) was expressed at higher abundance in the surface mucous cells and mucous neck cells, which expressed NHE-1, than in the parietal cells, which expressed AE2. The morphological evidence identified AE2 as a major parietal cell anion exchanger, whereas NHE-1 and CA II colocalized in mucous neck, chief, and surface mucous cells. We propose that all three of these cell types contribute to gastric bicarbonate secretion.

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Loss of Parietal Cell‐Expressed Sonic Hedgehog Results in Hypochlorhydria that is Associated with Altered Gastrointestinal Microbiota and Epithelial Morphology

The FASEB Journal ◽

10.1096/fasebj.25.1_supplement.1121.5 ◽

2011 ◽

Vol 25 (S1) ◽

Author(s):

Melinda A Engevik ◽

Yana Zavros ◽

Roger T Worrell

Keyword(s):

Sonic Hedgehog ◽

Parietal Cell ◽

Gastrointestinal Microbiota ◽

Epithelial Morphology

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The Acid-Secreting Parietal Cell as an Endocrine Source of Sonic Hedgehog During Gastric Repair

Endocrinology ◽

10.1210/en.2013-1483 ◽

2013 ◽

Vol 154 (12) ◽

pp. 4627-4639 ◽

Cited By ~ 18

Author(s):

Amy C. Engevik ◽

Rui Feng ◽

Li Yang ◽

Yana Zavros

Keyword(s):

Sonic Hedgehog ◽

Parietal Cell ◽

Plasma Concentrations ◽

Gastric Epithelium ◽

Gastric Ulcers ◽

Gastric Injury ◽

Gastric Tissue ◽

Β Subunit ◽

Exon 2 ◽

Acid Secreting

Sonic Hedgehog (Shh) has been shown to regulate wound healing in various tissues. Despite its known function in tissue regeneration, the role of Shh secreted from the gastric epithelium during tissue repair in the stomach remains unknown. Here we tested the hypothesis that Shh secreted from the acid-secreting parietal cell is a fundamental circulating factor that drives gastric repair. A mouse model expressing a parietal cell-specific deletion of Shh (PC-ShhKO) was generated using animals bearing loxP sites flanking exon 2 of the Shh gene (Shhflx/flx) and mice expressing a Cre transgene under the control of the H+,K+-ATPase β-subunit promoter. Shhflx/flx, the H+,K+-ATPase β-subunit promoter, and C57BL/6 mice served as controls. Ulcers were induced via acetic acid injury. At 1, 2, 3, 4, 5, and 7 days after the ulcer induction, gastric tissue and blood samples were collected. Parabiosis experiments were used to establish the effect of circulating Shh on ulcer repair. Control mice exhibited an increased expression of Shh in the gastric tissue and plasma that correlated with the repair of injury within 7 days after surgery. PC-ShhKO mice showed a loss of ulcer repair and reduced Shh tissue and plasma concentrations. In a parabiosis experiment whereby a control mouse was paired with a PC-ShhKO littermate and both animals subjected to gastric injury, a significant increase in the circulating Shh was measured in both parabionts. Elevated circulating Shh concentrations correlated with the repair of gastric ulcers in the PC-ShhKO parabionts. Therefore, the acid-secreting parietal cell within the stomach acts as an endocrine source of Shh during repair.

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The sld mutation is specific for sublingual salivary mucous cells and disrupts apomucin gene expression

Physiological Genomics ◽

10.1152/physiolgenomics.00151.2002 ◽

2003 ◽

Vol 14 (2) ◽

pp. 95-106 ◽

Cited By ~ 15

Author(s):

M. A. Fallon ◽

L. R. Latchney ◽

A. R. Hand ◽

A. Johar ◽

P. A. Denny ◽

...

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Mucous Cell ◽

Phenotypic Expression ◽

Secretory Protein ◽

Recessive Mutation ◽

Mucous Cells ◽

Age Related ◽

Serous Cell ◽

Cell Expression

NFS/N- sld mice harbor a spontaneous autosomal recessive mutation, sld (sublingual gland differentiation arrest) and histologically display attenuated mucous cell expression in sublingual glands (Hayashi et al. Am J Pathol 132: 187–191, 1988). Because altered serous demilune cell expression is unknown, we determined the phenotypic expression of this cell type in mutants. Moreover, we evaluated whether absence of glycoconjugate staining in 3-day-old mutant glands is related to disruption in apomucin gene expression and/or to posttranslational glycosylation events. Serous cell differentiation is unaffected, determined morphologically and by serous cell marker expression (PSP, parotid secretory protein; and Dcpp, demilune cell and parotid protein). Conversely, apical granules in “atypical” exocrine cells of mutant glands are PSP and mucin negative, but contain abundant SMGD (mucous granule marker). Age-related appearance of mucous cells is associated with expression of apomucin gene products, whereas SMGD expression is unaltered. “Atypical” cells thus appear specified to a mucous cell fate but do not synthesize mucin glycoproteins unless selectively induced postnatally, indicating the sld mutation disrupts apomucin transcriptional regulation and/or decreases apomucin mRNA stability.

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Cytoplasmic Invaginations in Trophoblasts and Epithelial Cells of Rat

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010006667x ◽

1971 ◽

Vol 29 ◽

pp. 524-525

Author(s):

Iracema M. Baccarini

Keyword(s):

Osmium Tetroxide ◽

Uranyl Acetate ◽

Nuclear Inclusions ◽

Mucous Cells ◽

Electron Microscopic ◽

Cervical Epithelium ◽

Intact Membrane ◽

Microscopic Studies ◽

Abnormal Cells ◽

Nuclear Features

Some morphological nuclear features (invaginations) in normal and abnormal cells have been described in several electron microscopic studies. They have been referred to by others as blebs, loops, pockets, sheets, bodies, nuclear inclusions and cytoplasmic invaginations. Identical appearing structures were found in cells of the uterine cervical epithelium, in trophoblasts of blastocysts and in trophoblasts of rat placenta.Methods. Uterine cervix (normal rats), rat placenta (9-10 days gestation) and blastocyst were placed in 3% glutarahdehyde for 3 hours. The tissue was washed in phosphate buffer for 24 hours, postfixed in 1%. buffered osmium tetroxide for 1-2 hours and embedded in epon araldite. Sections were double stained with uranyl acetate and lead citrate and viewed in E. M. Siemens 200.Observations. Nuclear invaginations were found in basal, parabasal and mucous cells of the cervix epithelium, in trophoblasts of blastocyst and in trophoblasts of placenta. An oval, round or elongated invagination contained heterogenously cytoplasm surrounded by a double intact membrane; usually several invaginations were found in the same nucleus.

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