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Notch activated protective signaling in damaged mammalian myocardium


Rebuilding the human myocardium following pathological injury remains a significant challenge both at the level of basic research and clinical application. In the last decade, cell based therapy has emerged as a promising option for repairing damaged heart tissue, but a universally available treatment still eludes the medical profession. The work presented here investigates the cardiac response to injury in the context of crosstalk between stem cell and survival kinase signaling. The hypothesis of this thesis is that activated Notch participates in a HGF/PI3K/Akt mediated survival signaling response to cardiac injury, and that Notch signaling drives cardiac differentiation of cardiac progenitor cells (CPCs). Notch, a critical cue in the developing heart, is activated in damaged myocardium. Likewise, following myocardial infarction, c-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), colocalizes with activated in nuclei of surviving cardiomyocytes. HGF stimulates Notch activity in neonatal rat cardiomyocytes (NRCMs) when applied in vitro and when injected into the intact heart. Moreover, exogenous Notch increases levels of cardiac phospho-Akt both in vitro and in vivo. Genetic tools were developed to manipulate activated Notch signaling and investigate regenerative/survival signaling crosstalk in intact heart as well as cardiac progenitor cells. A regulatable, intracellular Notch (KNIC) fused to the mutated estrogen receptor (mER) was created and tested for induction by tamoxifen. KNICmER was engineered into adenovirus for transient expression and lentivirus for stable integration into cardiac progenitor cells. Likewise, cardiac specific transgenic mice were created expressing KNICmER, and this construct will be subcloned downstream of the c-kit promoter to create a transgenic line with regulatable Notch activity in the progenitor population. These reagents will be applied in future studies aimed at improving the inherent reparative capacity of the mammalian heart as well as enhancing the regenerative success of adoptive transfer of cardiac progenitor cells into the damaged myocardium. Overall, this study demonstrates that activated Notch participates in cardiac protection following pathologic injury, in part by activation of the PI3K/Akt survival pathway, and that activated Notch also impacts cardiac progenitors by pushing them toward a cardiogenic lineage

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