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Rejuvenation of Helicobacter pylori-Associated Atrophic Gastritis Through Concerted Actions of Placenta-Derived Mesenchymal Stem Cells Prevented Gastric Cancer.

ABSTRACT: Chronic Helicobacter pylori infection causes gastric cancer via the progression of precancerous chronic atrophic gastritis (CAG). Therefore, repairing gastric atrophy could be a useful strategy in preventing H. pylori-associated gastric carcinogenesis. Although eradication of the bacterial pathogen offers one solution to this association, this study was designed to evaluate an alternative approach using mesenchymal stem cells to treat CAG and prevent carcinogenesis. Here, we used human placenta-derived mesenchymal stem cells (PD-MSCs) and their conditioned medium (CM) to treat H. pylori-associated CAG in a mice/cell model to explore their therapeutic effects and elucidate their molecular mechanisms. We compared the changes in the fecal microbiomes in response to PD-MSC treatments, and chronic H. pylori-infected mice were given ten treatments with PD-MSCs before being sacrificed for end point assays at around 36 weeks of age. These animals presented with significant reductions in the mean body weights of the control group, which were eradicated following PD-MSC treatment (p < 0.01). Significant changes in various pathological parameters including inflammation, gastric atrophy, erosions/ulcers, and dysplastic changes were noted in the control group (p < 0.01), but these were all significantly reduced in the PD-MSC/CM-treated groups. Lgr5+, Ki-67, H⁺/K⁺-ATPase, and Musashi-1 expressions were all significantly increased in the treated animals, while inflammatory mediators, MMP, and apoptotic executors were significantly decreased in the PD-MSC group compared to the control group (p < 0.001). Our model showed that H. pylori-initiated, high-salt diet-promoted gastric atrophic gastritis resulted in significant changes in the fecal microbiome at the phylum/genus level and that PD-MSC/CM interventions facilitated a return to more normal microbial communities. In conclusion, administration of PD-MSCs or their conditioned medium may present a novel rejuvenating agent in preventing the progression of H. pylori-associated premalignant lesions.

SUBMITTER: Park JM

PROVIDER: S-EPMC8416416 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Helicobacter pylori colonization of the human stomach is a strong risk factor for gastric cancer. To investigate H. pylori-induced gastric molecular alterations, we used a Mongolian gerbil model of gastric carcinogenesis. Histologic evaluation revealed varying levels of atrophic gastritis (a premalignant condition characterized by parietal and chief cell loss) in H. pylori-infected animals, and transcriptional profiling revealed a loss of markers for these cell types. We then assessed the spatial distribution and relative abundance of proteins in the gastric tissues using imaging mass spectrometry and liquid chromatography with tandem mass spectrometry. We detected striking differences in the protein content of corpus and antrum tissues. Four hundred ninety-two proteins were preferentially localized to the corpus in uninfected animals. The abundance of 91 of these proteins was reduced in H. pylori-infected corpus tissues exhibiting atrophic gastritis compared with infected corpus tissues exhibiting non-atrophic gastritis or uninfected corpus tissues; these included numerous proteins with metabolic functions. Fifty proteins localized to the corpus in uninfected animals were diffusely delocalized throughout the stomach in infected tissues with atrophic gastritis; these included numerous proteins with roles in protein processing. The corresponding alterations were not detected in animals infected with a H. pylori ∆cagT mutant (lacking Cag type IV secretion system activity). These results indicate that H. pylori can cause loss of proteins normally localized to the gastric corpus as well as diffuse delocalization of corpus-specific proteins, resulting in marked changes in the normal gastric molecular partitioning into distinct corpus and antrum regions.IMPORTANCEA normal stomach is organized into distinct regions known as the corpus and antrum, which have different functions, cell types, and gland architectures. Previous studies have primarily used histologic methods to differentiate these regions and detect H. pylori-induced alterations leading to stomach cancer. In this study, we investigated H. pylori-induced gastric molecular alterations in a Mongolian gerbil model of carcinogenesis. We report the detection of numerous proteins that are preferentially localized to the gastric corpus but not the antrum in a normal stomach. We show that stomachs with H. pylori-induced atrophic gastritis (a precancerous condition characterized by the loss of specialized cell types) exhibit marked changes in the abundance and localization of proteins normally localized to the gastric corpus. These results provide new insights into H. pylori-induced gastric molecular alterations that are associated with the development of stomach cancer.

Project description:Background and aimsMicroRNAs (miRNAs) are known for their function as translational regulators of tumor suppressor or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs related genes have been shown to affect the regulatory capacity of miRNAs and were linked with gastric cancer (GC) and premalignant gastric conditions. The purpose of this study was to evaluate potential associations between miRNA-related gene polymorphisms (miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608) and the presence of GC or high risk atrophic gastritis (HRAG) in European population.MethodsGene polymorphisms were analyzed in 995 subjects (controls: n = 351; GC: n = 363; HRAG: n = 281) of European descent. MiR-27a T>C (rs895819), miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913), miR-492 G>C (rs2289030) and miR-608 C>G (rs4919510) SNPs were genotyped by RT-PCR.ResultsOverall, SNPs of miRNAs were not associated with the presence of GC or HRAG. We observed a tendency for miR-196a-2 CT genotype to be associated with higher risk of GC when compared to CC genotype, however, the difference did not reach the adjusted P-value (odds ratio (OR) - 1.46, 95% confidence interval (CI) 1.03-2.07, P = 0.032). MiR-608 GG genotype was more frequent in GC when compared to controls (OR -2.34, 95% CI 1.08-5.04), but significance remained marginal (P = 0.029). A similar tendency was observed in a recessive model for miR-608, where CC + CG vs GG genotype comparison showed a tendency for increased risk of GC with OR of 2.44 (95% CI 1.14-5.22, P = 0.021). The genotypes and alleles of miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 SNPs had similar distribution between histological subtypes of GC and were not linked with the presence of diffuse or intestinal-type GC.ConclusionsGene polymorphisms of miR-27a, miR-146a, miR-196a-2, miR-492, miR-492a and miR-608 were not associated with the presence of HRAG, GC or different histological subtypes of GC in European subjects.

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Rejuvenation of Helicobacter pylori-Associated Atrophic Gastritis Through Concerted Actions of Placenta-Derived Mesenchymal Stem Cells Prevented Gastric Cancer.

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