Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach.
Ontology highlight
ABSTRACT:
SUBMITTER: Huh WJ
PROVIDER: S-EPMC3708546 | biostudies-literature | 2012 Jan
REPOSITORIES: biostudies-literature
Publications
Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach.
Huh Won Jae WJ Khurana Shradha S SS Geahlen Jessica H JH Kohli Kavita K Waller Rachel A RA Mills Jason C JC
Gastroenterology 20111014 1
Tamoxifen, a selective estrogen receptor modulator, is widely used in research and clinically in patients. We find that treatment of normal mice with a single ≥3 mg/20 g body weight dose of tamoxifen leads to apoptosis of >90% of all gastric parietal cells (PCs) and metaplasia of zymogenic chief cells within 3 days. Remarkably, gastric histology returns to nearly normal by 3 weeks. Tamoxifen toxicity occurs by oral and intraperitoneal administration, in both sexes, in multiple strains, and does ...[more]
Similar Datasets
Project description:Gastric adenocarcinoma is one of the leading causes of cancer mortality worldwide. It arises through a stepwise process that includes prominent inflammation with expression of interferon-? (IFN-?) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-? under the control of the stomach-specific H(+)/K(+) ATPase ? promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN-? transgenic mice exhibited inflammation, expansion of myofibroblasts, loss of parietal and chief cells, spasmolytic polypeptide expressing metaplasia, and dysplasia. Proliferation was elevated in undifferentiated and metaplastic epithelial cells in H/K-IFN-? transgenic mice, and there was increased apoptosis. H/K-IFN-? mice had elevated levels of mRNA for IFN-? target genes and the pro-inflammatory cytokines IL-6, IL-1?, and tumor necrosis factor-?. Intracellular mediators of IFN-? and IL-6 signaling, pSTAT1 and pSTAT3, respectively, were detected in multiple cell types within stomach. H/K-IFN-? mice developed dysplasia as early as 3 months of age, and 4 of 39 mice over 1 year of age developed antral polyps or tumors, including one adenoma and one adenocarcinoma, which expressed high levels of nuclear ?-catenin. Our data identified IFN-? as a pivotal secreted factor that orchestrates complex changes in inflammatory, epithelial, and mesenchymal cell populations to drive pre-neoplastic progression in stomach; however, additional alterations appear to be required for malignant conversion.
| S-EPMC3509761 | biostudies-literature
Project description:OBJECTIVE:Alternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown. DESIGN:To determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice. RESULTS:Profiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss. CONCLUSIONS:Metaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.
| S-EPMC5681443 | biostudies-literature
Project description:Background & aimsTissue metaplasia is uncommon in adults because established cis-element programs resist rewiring. In Barrett's esophagus, the distal esophageal mucosa acquires a predominantly intestinal character, with notable gastric features, and is predisposed to developing invasive cancers. We sought to understand the chromatin underpinnings of Barrett's metaplasia and why it commonly displays simultaneous gastric and intestinal properties.MethodsWe profiled cis-regulatory elements with active histone modifications in primary human biopsy materials using chromatin immunoprecipitation followed by DNA sequencing. Mutations in Barrett's esophagus were examined in relation to tissue-specific enhancer landscapes using a random forest machine-learning algorithm. We also profiled open chromatin at single-cell resolution in primary Barrett's biopsy specimens using the assay for transposase-accessible chromatin. We used 1- and 2-color immunohistochemistry to examine protein expression of tissue-restricted genes.ResultsBarrett's esophagus bears epigenome fingerprints of human stomach and intestinal columnar, but not esophageal squamous, epithelia. Mutational patterns were best explained as arising on the epigenome background of active gastric cis-elements, supporting the view that adjoining stomach epithelium is a likely tissue source. Individual cells in Barrett's metaplasia coexpress gastric and intestinal genes, reflecting concomitant chromatin access at enhancers ordinarily restricted to one or the other epithelium. Protein expression of stomach-specific mucins; CLDN18; and a novel gastric marker, ANXA10, showed extensive tissue and subclonal heterogeneity of dual stomach-intestinal cell states.ConclusionsThese findings reveal mixed and dynamic tissue-restricted chromatin states and phenotypic heterogeneity in Barrett's esophagus. Pervasive intragland variation argues against stem-cell governance of this phenotype.
| S-EPMC8380686 | biostudies-literature
Project description:Calorie restriction (CR) without malnutrition increases life span and health span in multiple model organisms. In non-human and human primates, CR causes changes that protect against several age-related pathologies, reduces inflammation, and preserves or improves cell-mediated immunity. However, CR has also been shown to exhibit adverse effects on certain organs and systems, including the immune system, and to impact genetically different organisms of the same species differentially. Alternately, short periods of fasting followed by refeeding may result in the proliferation of bone marrow stem cells, suggesting a potential rejuvenation effect that could impact the hematopoietic compartment. However, the global consequences of CR followed by refeeding on the immune system have not been carefully investigated. Here, we show that individuals practicing long-term CR with adequate nutrition have markedly lower circulating levels of total leukocytes, neutrophils, lymphocytes, and monocytes. In 10-month-old mice, short-term CR lowered lymphocyte cellularity in multiple lymphoid tissues, but not in bone marrow, which appears to be a site of influx, or a "safe haven" for B, NK, and T cells during CR. Cellular loss and redistribution was reversed within the first week of refeeding. Based on BrdU incorporation and Ki67 expression assays, repopulating T cells exhibited high proliferation in the refeeding group following CR. Finally, we demonstrated that the thymus was not essential for T cell repopulation following refeeding. These findings are of potential relevance to strategies to rejuvenate the immune system in mammals and warrant further investigation.
| S-EPMC6060198 | biostudies-literature
Project description:Gastric cancer evolves in the setting of a pathologic mucosal milieu characterized by both loss of acid-secreting parietal cells and mucous cell metaplasias. Indeed, mucous cell metaplasia is considered the critical preneoplastic lesion for gastric cancer. Previous investigations have shown that infection of mice with Helicobacter felis or induction of acute parietal cell loss with the drug DMP-777 leads to the emergence of a type of metaplasia designated spasmolytic polypeptide-expressing metaplasia (SPEM). We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells.Taking advantage of the chief cell-restricted expression of Mist1-Cre-ER(T2), we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection.Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells.These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation.
| S-EPMC2997152 | biostudies-literature
Project description:Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in non-cutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis.Time- and context-dependent expression of PPL in various mouse models of hepatic and renal disorders were examined by immunohistochemistry, western blotting, and quantitative real-time polymerase chain reactions.The hepatic expression of PPL was significantly decreased in Fxr-/- mice. In contrast, the expression was dramatically increased during cholestasis, with massive PPL accumulation observed at the boundaries of hepatocytes in wild-type mice. Interestingly, the hepatic accumulation of PPL resulting from cholestasis was reversible. In addition, similar accumulation of PPL at cellular boundaries was found in epithelial cells around renal tubules upon ureteral obstruction.PPL may be involved in the temporal accommodation to fluid stasis in different tissues. Further examination of the roles for PPL may lead to the discovery of a novel mechanism for cellular protection by cytolinkers that is applicable to many tissues and in many contexts.
| S-EPMC3716950 | biostudies-literature
Project description: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.
| S-EPMC5391042 | biostudies-literature
Project description:Oxyntic atrophy in the stomach leads to chief cell transdifferentiation into spasmolytic polypeptide expressing metaplasia (SPEM). Investigations of preneoplastic metaplasias in the stomach are limited by the sole reliance on in vivo mouse models, owing to the lack of in vitro models for distinct normal mucosal lineages and metaplasias. Utilizing the Immortomouse, in vitro cell models of chief cells and SPEM were developed to study the characteristics of normal chief cells and metaplasia. Chief cells and SPEM cells isolated from Immortomice were cultured and characterized at both the permissive (33°C) and the nonpermissive temperature (39°C). Clones were selected on the basis of their transcriptional expression of specific stomach lineage markers (named ImChief and ImSPEM) and protein expression and growth were analyzed. The transcriptional expression profiles of ImChief and ImSPEM cells were compared further by using gene microarrays. ImChief cells transcriptionally express most chief cell markers and contain pepsinogen C and RAB3D-immunostaining vesicles. ImSPEM cells express the SPEM markers TFF2 and HE4 and constitutively secrete HE4. Whereas ImChief cells cease proliferation at the nonpermissive temperature, ImSPEM cells continue to proliferate at 39°C. Gene expression profiling of ImChief and ImSPEM revealed myelin and lymphocyte protein 2 (MAL2) as a novel marker of SPEM lineages. Our results indicate that the expression and proliferation profiles of the novel ImChief and ImSPEM cell lines resemble in vivo chief and SPEM cell lineages. These cell culture lines provide the first in vitro systems for studying the molecular mechanisms of the metaplastic transition in the stomach.
| S-EPMC4200317 | biostudies-literature
Project description:Type-I collagen self-assembles into a fibrillar gel at physiological temperature and pH to provide a cell-adhesive, supportive, structural network. As such, it is an attractive, popular scaffold for in vitro evaluations of cellular behavior and for tissue engineering applications. In this study, type-I collagen is modified to introduce methacrylate groups on the free amines of the lysine residues to create collagen methacrylamide (CMA). CMA retains the properties of collagen such as self-assembly, biodegradability, and natural bioactivity but is also photoactive and can be rapidly cross-linked or functionalized with acrylated molecules when irradiated with ultraviolet light in the presence of a photoinitiator. CMA also demonstrates unique temperature-dependent behavior. For natural type-I collagen, the overall structure of the fiber network remains largely static over time scales of a few hours upon heating and cooling at temperatures below its denaturation point. CMA, however, is rapidly thermoreversible and will oscillate between a liquid macromer suspension and a semisolid fibrillar hydrogel when the temperature is modulated between 10 and 37 °C. Using a series of mechanical, scattering, and spectroscopic methods, we demonstrate that structural reversibility is manifest across multiple scales from the protein topology of the triple helix up through the rheological properties of the CMA hydrogel. Electron microscopy imaging of CMA after various stages of heating and cooling shows that the canonical collagen-like D-periodic banding ultrastructure of the fibers is preserved. A rapidly thermoreversible collagen-based hydrogel is expected to have wide utility in tissue engineering and drug delivery applications as a biofunctional, biocompatible material. Thermal reversibility also makes CMA a powerful model for studying the complex process of hierarchical collagen self-assembly.
| S-EPMC4172302 | biostudies-literature
Project description:Gastric intestinal metaplasia (IM) is a highly prevalent preneoplastic lesion; however, the molecular mechanisms regulating its development remain unclear. We have previously shown that a population of cells expressing the intestinal stem cell (ISC) marker LGR5 increases remarkably in IM. In this study, we further investigated the molecular characteristics of these LGR5+ cells in IM by examining the expression profile of several ISC markers. Notably, we found that ISC markers-including OLFM4 and EPHB2-are positively associated with the CDX2 expression in non-tumorous gastric tissues. This finding was confirmed in stomach lesions with or without metaplasia, which demonstrated that OLFM4 and EPHB2 expression gradually increased with metaplastic progression. Moreover, RNA in situ hybridization revealed that LGR5+ cells coexpress several ISC markers and remained confined to the base of metaplastic glands, reminiscent to that of normal intestinal crypts, whereas those in normal antral glands expressed none of these markers. Furthermore, a large number of ISC marker-expressing cells were diffusely distributed in gastric adenomas, suggesting that these markers may facilitate gastric tumorigenesis. In addition, Barrett's esophagus (BE)-which is histologically similar to intestinal metaplasia-exhibited a similar distribution of ISC markers, indicating the presence of a stem cell population with intestinal differentiation potential. In conclusion, we identified that LGR5+ cells in gastric IM and BE coexpress ISC markers, and exhibit the same expression profile as those found in normal intestinal crypts. Taken together, these results implicate an intestinal-like stem cell population in the pathogenesis of IM, and provide an important basis for understanding the development and maintenance of this disease.
| S-EPMC4440782 | biostudies-literature