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

Jong Min Park,Ki Baik Hahm,Young Min Han

doi:10.3389/fphar.2021.675443

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.

Highlights

There has been a broad paradigm shift in our understanding of gastric cancer prevention over the last three decades
Since we already have an established H. pylori–induced chronic atrophic gastritis (CAG) mouse, which relies on an H. pylori infection–initiated, high-salt diet–promoted mouse model (Nam et al, 2004a; Nam et al, 2004b; Park et al, 2014; Jeong et al, 2015; Han et al, 2016; An et al, 2019), we went on to design this experiment to document the ameliorating action of placenta-derived mesenchymal stem cells (PD-mesenchymal stem cells (MSCs)) or their conditioned medium (CM) against H. pylori–induced CAG
The resected stomachs from each group were subjected to pathological evaluation, and the total pathological scores describing gastric inflammation, gastric atrophy, and tumorigenesis were significantly decreased in the PD-MSC–treated group compared to the control group (Supplementary Table 2; p < 0.001, Figure 1D)

Summary

Introduction

There has been a broad paradigm shift in our understanding of gastric cancer prevention over the last three decades. Most gastric carcinomas follow a documented and discernable cascade of precursor lesions, slowly progressing from the premalignant stages of CAG, to intestinal metaplasia (IM), and dysplasia to gastric carcinoma (de Vries et al, 2007; Moss, 2017), and since most of these lesions are a direct result of the chronic inflammation of gastric mucosa associated with H. pylori infection, multiple clinical interventions and trials have been implemented to prevent this cascade and detour the progression of this disease (Sipponen and Kimura, 1994; Correa and Piazuelo, 2012; Correa, 2013; Piazuelo and Correa, 2013; Rugge et al, 2013). These interventions all rely on the theory that gastric cancers associated with H. pylori infection can be prevented by the application of antioxidants or equivalent therapies via their reduction of the premalignant lesions including CAG with IM and their so-called suspension of the gastric precancerous cascade

Methods

Results

Conclusion