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Inflammation-Induced Activation of Bone Marrow-Derived Mesenchymal Stem Cells During Gastric Disease

Donnelly, Jessica M.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613253

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
Background and Significance: Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent stromal cells that have the capacity to differentiate into hepatocytes, neurons, epithelial cells, myocytes and fibroblasts depending on the environmental cues. However, while MSCs are instrumental in the process of tissue repair these cells can also be activated into a cancer-promoting phenotype. While it is known that chronic gastric inflammation serves as a trigger for MSC transformation, the precise mechanism through which this occurs is unclear. Thus, identifying the process by which MSCs undergo malignant transformation in response to chronic inflammation is critical for our understanding of cancer development. Sonic hedgehog (Shh) is a morphogen typically recognized for its role in development, and more recently in maintenance of normal adult gastrointestinal differentiation and architecture. In states of chronic inflammation, as with Helicobacter pylori (H. pylori) infection, endogenous Shh signaling in the gastric mucosa is suppressed, but later re-emerges in the tumor microenvironment. Cytokines, such as interferon gamma (IFN?) and transforming growth factor beta (TGFß) are implicated in this process. In addition, the recruitment of MSCs to the gastric mucosa occurs in conjunction with the morphological changes characterized by high levels of re-emerging Shh expression. Autocrine activation of the Hedgehog (Hh) pathway promotes the aberrant proliferation of MSCs which may lead to genomic instability and alterations in differentiation. Therefore, we hypothesize that MSCs recruited to the stomach may be the source of elevated Shh within the gastric mucosa during cancer development. Objectives: 1) To identify the mechanism of Shh induction within MSCs, 2) to identify the role of Shh signaling in the development of a malignant MSC phenotype and 3) identify the role of MSC-derived Shh in the precancerous and neoplastic gastric mucosa. Major findings: Studies using the gastrin-deficient (GKO) mouse model of chronic gastritis and gastric cancer development showed that gastric and systemic TGFß increased Shh production and activated the Hh pathway in MSCs through an autocrine mechanism. Elevated Shh correlated with malignant transformation of MSCs within the bone marrow compartment. Exogenous IFN? produced a similar effect, both in vitro and in vivo, whereby autocrine Hh pathway activation promoted increased MSC recruitment to the gastric mucosa and the induction of chemokine (C-X-C motif receptor 4 (CXCR4) expression. Exogenous IFN? leads to increased circulating chemokine stromal-derived factor-1 (SDF-1). MSC-derived Shh promoted proliferation of CD44+ gastric epithelial cells as well as c-kit+ interstitial cells of Cajal (ICCs), leading to gastrointestinal stromal tumor development. Conclusions: The malignant transformation of MSCs occurs in the bone marrow through the convergence of multiple inflammatory signaling pathways. Increased Shh expression and autocrine Hh pathway activation promotes enhanced MSC proliferation and recruitment to sites of chronic inflammation. Once recruited to the gastric mucosa, MSC-derived Shh is capable of targeting the aberrant proliferation of tissue and cancer stem cell-like populations.
Yana Zavros, Ph.D. (Committee Chair)
Sohaib Khan, Ph.D. (Committee Member)
Marshall Montrose, Ph.D. (Committee Member)
Noah Shroyer, Ph.D. (Committee Member)
Susan Waltz, Ph.D. (Committee Member)
203 p.
Physiological Psychology
Bone marrow-derived mesenchymal stem cell; Gastric cancer; Sonic hedgehog

Recommended Citations

Citations

  • Donnelly, J. M. (2013). Inflammation-Induced Activation of Bone Marrow-Derived Mesenchymal Stem Cells During Gastric Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613253

    APA Style (7th edition)

  • Donnelly, Jessica. Inflammation-Induced Activation of Bone Marrow-Derived Mesenchymal Stem Cells During Gastric Disease. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613253.

    MLA Style (8th edition)

  • Donnelly, Jessica. "Inflammation-Induced Activation of Bone Marrow-Derived Mesenchymal Stem Cells During Gastric Disease." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613253

    Chicago Manual of Style (17th edition)

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© 2013, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.