The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
The orderly differentiation of cell lineages within gastric glands is regulated by a complicated interplay of local mucosal growth factors and hormones. Histamine secreted from enterochromaffin-like cells plays an important role in not only stimulated gastric acid secretion but also coordination of intramucosal growth and lineage differentiation. We have examined histidine-decarboxylase (HDC)-deficient mice, which lack endogenous histamine synthesis, to evaluate the influence of histamine on differentiation of fundic mucosal lineages and the development of metaplasia following induction of acute oxyntic atrophy. Stomachs from HDC-deficient mice and wild-type mice were evaluated at 8 wk and 12 mo of age. DMP-777 was administrated orally to 6-wk-old mice for 1 to 14 days. Sections of gastric mucosa were stained with antibodies against Mist1, intrinsic factor, H/K-ATPase, trefoil factor 2 (TFF2), chromogranin A, and Ext1 and for the cell cycle marker phospho-histone H3. HDC-deficient mice at 8 wk of age demonstrated a prominent increase in chief cells expressing Mist1 and intrinsic factor. Importantly Mist1-positive mature chief cells were present in the midgland region as well as at the bases of fundic glands, indicating a premature differentiation of chief cells. Mice dually deficient for both HDC and gastrin showed a normal distribution of chief cells in fundic glands. Treatment of HDC-deficient mice with DMP-777 led to loss of parietal cells and an accelerated and exaggerated emergence of mucous cell metaplasia with the presence of dual intrinsic factor and TFF2-expressing cells throughout the gland length, indicative of the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM) from chief cells. These findings indicate that histamine, in concert with gastrin, regulates the appropriate differentiation of chief cells from mucous neck cells as they migrate toward the bases of fundic glands. Nevertheless, histamine is not required for emergence of SPEM following acute oxyntic atrophy.
BACKGROUND & AIMS - Loss of gastric parietal cells is a critical precursor to gastric metaplasia and neoplasia. However, the origin of metaplasia remains obscure. Acute parietal cell loss in gastrin-deficient mice treated with DMP-777 leads to the rapid emergence of spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia (SPEM) from the bases of fundic glands. We now sought to characterize more definitively the pathway for emergence of SPEM.
METHODS - Emerging SPEM lineages in gastrin-deficient mice treated with DMP-777 were examined for immunolocalization of TFF2, intrinsic factor, and Mist1, and morphologically with electron microscopy. Emerging SPEM was isolated with laser-capture microdissection and RNA was analyzed using gene microarrays. Immunohistochemistry in mouse and human samples was used to confirm up-regulated transcripts.
RESULTS - DMP-777-induced SPEM was immunoreactive for TFF2 and the differentiated chief cell markers, Mist1 and intrinsic factor, suggesting that SPEM derived from transdifferentiation of chief cells. Microarray analysis of microdissected SPEM lineages induced by DMP-777 showed up-regulation of transcripts associated with G1/S cell-cycle transition including minichromosome maintenance deficient proteins, as well as a number of secreted factors, including human epididymis 4 (HE4). HE4, which was absent in the normal stomach, was expressed in SPEM of human and mouse and in intestinal metaplasia and gastric cancer in human beings.
CONCLUSIONS - Although traditionally metaplasia was thought to originate from normal mucosal progenitor cells, these studies indicate that SPEM evolves through either transdifferentiation of chief cells or activation of a basal cryptic progenitor. In addition, induction of metaplasia elicits the expression of secreted factors, such as HE4, relevant to gastric preneoplasia.
BACKGROUND & AIMS - The loss of parietal cells from the gastric mucosa (oxyntic atrophy) is a critical step in the pathogenesis of chronic gastritis and gastric adenocarcinoma. Parietal cells are known to secrete epidermal growth factor receptor (EGFR) ligands, which are critical regulators of differentiation in the gastric mucosa. Although all of the actions of EGFR ligands are mediated through a common EGFR protein, individual ligands may produce different physiologic responses. Previous investigations have suggested that a deficit in EGFR signaling in waved-2 mice accelerates the emergence of metaplasia after induction of acute oxyntic atrophy. We sought to determine whether specific EGFR ligands regulate the metaplastic response to oxyntic atrophy.
METHODS - To induce spasmolytic polypeptide-expressing metaplasia (SPEM), amphiregulin (AR) and transforming growth factor-alpha-deficient mice and their wild-type littermates were treated with DMP-777 for 0-14 days and for 14 days followed by 14 days of recovery off drug. We evaluated the gastric mucosal response to oxyntic atrophy using cell lineage-specific markers.
RESULTS - Although loss of transforming growth factor-alpha did not influence the induction of SPEM, loss of AR caused an acceleration and amplification in the induction of SPEM after acute oxyntic atrophy. Trefoil factor family 2/spasmolytic polypeptide and intrinsic factor dual-immunostaining cells significantly increased in the SPEM of AR-deficient mice. At the bases of glands, intrinsic factor immunoreactive cells also were costained for 5-bromo-2'-deoxyuridine, suggesting their re-entry into the cell cycle.
CONCLUSIONS - The absence of AR promoted the rapid emergence of SPEM in response to oxyntic atrophy.
In addition to their role in gastric acid secretion, parietal cells secrete a number of growth factors that may influence the differentiation of other gastric lineages. Indeed, oxyntic atrophy is considered the most significant correlate with increased risk for gastric adenocarcinoma. We studied the alterations in gastric mucosal lineages elicited by acute oxyntic atrophy induced by treatment of C57BL/6 and gastrin-deficient mice with the parietal cell protonophore [S-(R*,S*)]-N-[1-(1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2-[4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidinecarboxamide (DMP-777). In both wild-type and gastrin knockout mice, DMP-777 elicited the rapid loss of parietal cells within 2 days of treatment. In wild-type mice, oxyntic atrophy was accompanied by a rapid increase in 5-bromo-2'-deoxyuridine-labeled proliferative cells and attendant increase in surface cell numbers. However, gastrin knockout mice did not demonstrate significant foveolar hyperplasia and showed a blunted proliferative response. After 7 days of treatment in wild-type mice, a second proliferative population emerged at the base of fundic glands along with the development of a mucous cell metaplasia expressing TFF2/spasmolytic polypeptide (SPEM). However, in gastrin knockout mice, SPEM expressing both TFF2 mRNA and protein developed after only 1 day of DMP-777 treatment. In wild-type mice, all changes induced by DMP-777 were reversed 14 days after cessation of treatment. In gastrin-deficient mice, significant SPEM was still present 14 days after the cessation of treatment. The results indicate that foveolar hyperplasia requires the influence of gastrin, whereas SPEM develops in response to oxyntic atrophy independent of gastrin, likely through transdifferentiation of chief cells.