Yanfang Chen (Advisor), David Cool (Committee Member), Kate Excoffon (Committee Member), Bradley Jacobs (Committee Member), James Olson (Committee Member)
Doctor of Philosophy (PhD)
Ischemic stroke (IS) is a major cause of death and disability with limited and less effective therapeutics. Transplantation of stem cells, such as neuronal progenitor cells (NPCs) and endothelial progenitor cells (EPCs), is promising for treating IS. It is well known that neurogenesis and angiogenesis are critical for cerebral repair following ischemic injury. However, whether co-transplantation of EPCs and NPCs has synergistic effects remains unclarified. In addition, the PI3K/Akt pathway participates in modulating a widely range of cellular functions such as anti-apoptotic and anti-oxidant. The signal pathways responsible for the effects of grafted NPCs and EPCs are also waiting for in-depth investigation. The purpose of this dissertation was to determine whether co-transplantation of EPCs and NPCs has synergistic effects on IS via activation of the PI3K/Akt pathway. This project was divided into two parts. Part 1: By using hypoxia/reoxygenation-induced ECs and neurons (SH-SY5Y cells) injury models in the transwell co-culture system, we found that co-culture with EPCs and NPCs synergistically 1) reduced reactive oxygen species (ROS) over-production and apoptosis in ECs and neurons; 2) up-regulated the protein expressions of VEGF and VEGFR2 in ECs, and of BDNF and TrkB in neurons; 3) up-regulated the expression of p-Akt/Akt in ECs and neurons. These effects were abrogated by the PI3K inhibitor (LY294002). Part 2: By employing a mouse model of IS, we found that co-transplantation of EPCs and NPCs synergistically 1) improved motor function; 2) alleviated the pathological indexes (infarct volume, cell apoptosis and ROS production) and improved cerebral microvascular density; 3) increased the levels of VEGF and BDNF, as well as p-Akt/Akt in the ipsilateral brain in both subacute and chronic phases; 4) increased IL-10 level, whereas decreased plasma TNF-a and IL-1a levels in subacute phase; 5) promoted neurogenesis and angiogenesis. All of these effects were abolished by LY294002. Taken together, these data demonstrate that co-transplantation of EPCs and NPCs augments the therapeutic efficacies for IS via synergistically activating the PI3K/Akt pathway, which provides a novel therapeutic strategy for IS.
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