Department of Medicine, Division of Gastroenterology
Animals; Cell Proliferation; Cell Transformation, Neoplastic; Chemokine CXCL12; Focal Adhesions; Gastric Mucosa; Gene Knockdown Techniques; Gene Silencing; Hedgehog Proteins; Interferon-gamma; Mesenchymal Stromal Cells; Mice; Signal Transduction; Stomach
Cancer Biology | Cellular and Molecular Physiology | Digestive System | Gastroenterology
Studies using Helicobacter-infected mice show that bone marrow-derived mesenchymal stem cells (MSCs) can repopulate the gastric epithelium and promote gastric cancer progression. Within the tumor microenvironment of the stomach, pro-inflammatory cytokine interferon-gamma (IFNgamma) and Sonic hedgehog (Shh) are elevated. IFNgamma is implicated in tumor proliferation via activation of the Shh signaling pathway in various tissues but whether a similar mechanism exists in the stomach is unknown. We tested the hypothesis that IFNgamma drives MSC proliferation and recruitment, a response mediated by Shh signaling. The current study uses transplantation of an in vitro transformed mesenchymal stem cell line (stMSC(vect)), that over-expresses hedgehog signaling, in comparison to non-transformed wild-type MSCs (wtMSCs), wtMSCs transfected to over-express Shh (wtMSC(Shh)), and stMSCs transduced with lentiviral constructs containing shRNA targeting the Shh gene (stMSC(ShhKO)). The effect of IFNgamma on MSC proliferation was assessed by cell cycle analysis in vitro using cells treated with recombinant IFNgamma (rmIFNgamma) alone, or in combination with anti-Shh 5E1 antibody, and in vivo using mice transplanted with MSCs treated with PBS or rmIFNgamma. In vitro, IFNgamma significantly increased MSC proliferation, a response mediated by Shh that was blocked by 5E1 antibody. The MSC population collected from bone marrow of PBS- or IFNgamma-treated mice showed that IFNgamma significantly increased the percentage of all MSC cell lines in S phase, with the exception of the stMSCs(ShhKO) cells. While the MSC cell lines with intact Shh expression were recruited to the gastric mucosa in response to IFNgamma, stMSCs(ShhKO) were not. Hedgehog signaling is required for MSC proliferation and recruitment to the stomach in response to IFNgamma.
DOI of Published Version
PLoS One. 2013 Sep 19;8(9):e75225. doi: 10.1371/journal.pone.0075225. eCollection 2013. Link to article on publisher's site
Donnelly, Jessica M.; Chawla, Ambreesh; Houghton, JeanMarie; and Zavros, Yana, "Sonic hedgehog mediates the proliferation and recruitment of transformed mesenchymal stem cells to the stomach" (2013). University of Massachusetts Medical School Faculty Publications. 570.
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