Gastritis promotes an activated bone marrow-derived mesenchymal stem cell with a phenotype reminiscent of a cancer-promoting cell

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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 (TGFb) 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 TGFb 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.

Original languageEnglish (US)
Pages (from-to)569-582
Number of pages14
JournalDigestive diseases and sciences
Volume59
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Keywords

  • Cancer stem cell
  • Helicobacter pylori
  • Sonic hedgehog
  • TGFb

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology

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