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Gastritis Promotes an Activated Bone Marrow-Derived Mesenchymal Stem Cell with a Phenotype Reminiscent of a Cancer-Promoting Cell

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Abstract

Background

Bone marrow-derived mesenchymal stem cells (BM-MSCs) promote gastric cancer in response to gastritis. In culture, BM-MSCs are prone to mutation with continued passage but it is unknown whether a similar process occurs in vivo in response to gastritis.

Aim

The purpose of this study was to identify the role of chronic gastritis in the transformation of BM-MSCs leading to an activated cancer-promoting phenotype.

Methods

Age matched C57BL/6 (BL/6) and gastrin deficient (GKO) mice were used for isolation of stomach, serum and mesenchymal stem cells (MSCs) at 3 and 6 months of age. MSC activation was assessed by growth curve analysis, fluorescence-activated cell sorting and xenograft assays. To allow for the isolation of bone marrow-derived stromal cells and assay in response to chronic gastritis, IRG/Vav-1Cre mice that expressed both enhanced green fluorescent protein-expressing hematopoietic cells and red fluorescent protein-expressing stromal cells were generated. In a parabiosis experiment, IRG/Vav-1Cre mice were paired to either an uninfected Vav-1Cre littermate or a BL/6 mouse inoculated with Helicobacter pylori.

Results

GKO mice displayed severe atrophic gastritis accompanied by elevated gastric tissue and circulating transforming growth factor beta (TGFβ) by 3 months of age. Compared to BM-MSCs isolated from uninflamed BL/6 mice, BM-MSCs isolated from GKO mice displayed an increased proliferative rate and elevated phosphorylated-Smad3 suggesting active TGFβ signaling. In xenograft assays, mice injected with BM-MSCs from 6-month-old GKO animals displayed tumor growth. RFP+ stromal cells were rapidly recruited to the gastric mucosa of H. pylori parabionts and exhibited changes in gene expression.

Conclusions

Gastritis promotes the in vivo activation of BM-MSCs to a phenotype reminiscent of a cancer-promoting cell.

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Abbreviations

Shh:

Sonic hedgehog

GKO:

Gastrin-deficient mouse model

BL/6:

C57BL/6 mice

TGFβ:

Transforming growth factor beta

H. pylori :

Helicobacter pylori

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Acknowledgments

This work was supported by the American Cancer Society Research Scholar Award 119072-RSG-10-167-01-MPC (Y. Zavros), Albert J. Ryan Foundation Fellowship (J. Donnelly) and in part by the Digestive Health Center Cincinnati Children’s Medical Health Center (DHC: Bench to Bedside Research in Pediatric Digestive Disease) CHTF/SUB DK078392. We would like to acknowledge the assistance of Monica DeLay manager of the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center, supported in part by NIH AR-47363. All flow cytometric data were acquired using equipment maintained by the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center, supported in part by NIH AR-47363. We would also like to thank Dr. Linda Samuelson (Department of Molecular and Integrative Physiology, University of Michigan) for donating the gastrin-deficient mice.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert B. Sabin Way, Room 4255 MSB, Cincinnati, OH, 45267-0576, USA

    Jessica M. Donnelly, Amy C. Engevik, Melinda Engevik, Michael A. Schumacher, Li Yang, Roger T. Worrell & Yana Zavros

  2. Department of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Chang Xiao

Authors
  1. Jessica M. Donnelly
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  2. Amy C. Engevik
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  3. Melinda Engevik
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  5. Chang Xiao
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  6. Li Yang
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Correspondence to Yana Zavros.

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Donnelly, J.M., Engevik, A.C., Engevik, M. et al. Gastritis Promotes an Activated Bone Marrow-Derived Mesenchymal Stem Cell with a Phenotype Reminiscent of a Cancer-Promoting Cell. Dig Dis Sci 59, 569–582 (2014). https://doi.org/10.1007/s10620-013-2927-z

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