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Gene therapy and cell fusion enhances stem cell mediated cardiac repair
Quijada, Pearl Jennine
Cardiovascular disease is the leading cause of mortality in the United States. Myocardial infarction (MI) induces massive cellular death and leads to a decline in cardiac function. Cardiomyocytes have limited proliferative capacity sparking interests in molecular and cellular strategies to promote stem cell conversion into new cardiomyocytes. Cardiac progenitor cells (CPCs) are tissue resident stem cells that give rise to cardiomyogenic structures. Although, CPCs introduced into the heart confer improvements in cardiac function after MI, these effects are not sufficient to support complete heart regeneration and prevent heart failure. Studying molecular pathways that contribute to CPC survival and commitment is essential in advancing CPC based therapeutic approaches. Ca__/Calmodulin-dependent protein kinase II_B (CaMKII_B) regulates survival and growth in cardiomyocytes. However, the role of CaMKII_ in CPCs has not been previously explored. CPCs increase nuclear CaMKII after MI and in vitro differentiation suggesting that CaMKII_B contributes to the regulation of CPC commitment. Overexpression of CaMKII_B in CPCs reduces proliferation, enhances resistance to death and increases cardiac specific differentiation. CaMKII_B may serve as a novel modulatory kinase to promote CPC survival and commitment. Despite increasing use of stem cells for regenerative-based cardiac therapy, the optimal stem cell population(s) remains uncertain. In the past decade there has been increasing interest and characterization of stem cell populations reported to directly and/or indirectly contributes to cardiac regeneration through processes of cardiomyogenic commitment and / or release of cardioprotective paracrine factors. Future therapies require development of unprecedented concepts to enhance myocardial healing. Combinatorial cell therapy utilizing CPCs and bone marrow derived mesenchymal stem cells (MSCs) promote enhanced reparative functions in vivo. However, identifying cell specific mechanisms of cardiac repair are difficult using dual cell systems. Here, we performed cell fusion between CPCs and MSCs to obtain hybrids with combined cell characteristics called CardioChimeras. Our ideal cell therapy is to combine the beneficial properties of CPCs to undergo cardiac specific commitment as well as MSCs that foster an improved microenvironment with protective paracrine secretion.
Doctor of Philosophy (Ph.D.) University of California, San Diego and San Diego State University, 2015
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