There has been a great deal of excitement in the last few years over the potential therapeutic use of isolated stem cells to repair or regenerate diseased organs. Bone-marrow-derived mesenchymal stem cells (MSC) are currently being evaluated as a source of immature endothelial cells or angioblasts that can repair damaged vasculature. Hypoxia, or reduced oxygen tension, favors the differentiation of MSCs into cells capable of building new blood vessels. However, the classical hypoxia-induced angiogenic factors like vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are not fully capable of restoring this effect. The hypoxia-regulated factor, erythropoietin (Epo), is known to mediate differentiation of erythroblasts into mature red blood cells. More recently, Epo was reported to induce a pro-angiogenic phenotype in human endothelial cells. In cancer biology, Epo secretion has been implicated in tumor growth and angiogenesis of erythrocytic leukemia cells, hepatocellular carcinoma and several female breast and reproductive organ carcinomas. Tumor angiogenesis is critical for tumor growth and survival. The goal of this study is to test the hypothesis that local erythropoietin secretion following tissue exposure to hypoxia initiates a cascade of events in erythropoietin receptor bearing MSCs and endothelial cells that leads to their differentiation and contribution to new blood vessel formation facilitating malignant tumor development. To test this hypothesis the following aims are proposed:
Aim 1 Evaluate the effects of environmental cues given by Epo and/or hypoxia on the induction of a pro-angiogenic phenotype of treated MSC and endothelial cells and;
Aim 2 Determine the cellular responses of Epo and/or hypoxia -treated MSC and endothelial cells.
Aim 3 Establish an animal model of Kaposi's Sarcoma as a tool to characterize in vivo the pro-angiogenic potential of mesenchymal stem cells and endothelial cells and their contribution towards tumor angiogenesis. Defining these Epo-mediated events may lead to a better understanding of hypoxia driven angiogenic processes and the identification of novel targets for the design of improved cancer therapy. Apart from defining a new mechanism for tumor cell recruitment of blood vessels, successful completion of the proposed studies will contribute to our basic understanding of stem cells and how they might be valuable in gene therapy. Importantly, the information gained from this study may implicate Epo and EpoR signaling mechanisms as regulating angiogenesis and may particularly elucidate regulatory pathways controlling the cellular fate of mesenchymal stem cells.
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