UC San Diego

Tangible returns from cell and molecular therapeutic interventions to promote cardiac repair have been predominantly underwhelming at both basic research and clinical levels. The field of cardiovascular research would benefit tremendously from identification of optimal protein(s), signaling pathways and/or an optimal cell population to enhance cardiac repair. Cell fusion has been used to create novel therapeutic cellular effectors by incorporating beneficial characteristics of two different cardiac derived cells. Human CardioChimeras (hCCs) produced by fusion of c-kit+ cardiac interstitial cells with mesenchymal stem cells exhibited enhanced survival relative to the parent cells and promoted cardiomyocyte survival in response to serum deprivation. Feasibility of creating human hybrid cells prompts consideration of multiple possibilities to create novel chimeric cells derived from cells with desirable traits to promote healing in pathologically damaged myocardium. Enhancing cardiomyocyte survival is crucial to blunt deterioration of myocardial structure and function following pathological damage. PIM1 is a cardioprotective serine threonine kinase that promotes cardiomyocyte survival and antagonizes senescence through multiple concurrent molecular signaling cascades. In hematopoietic stem cells, PIM1 interacts with the receptor tyrosine kinase c-Kit to promote cell proliferation and survival. The relationship between PIM1 and c-Kit activity has not been explored in the myocardial context. The study presented in this dissertation delineated the interaction between PIM1 and c-Kit leading to enhanced protection of cardiomyocytes from stress. The mechanistic relationship between PIM1 and c-Kit in cardiomyocytes identifies a novel facet of cardioprotection regulated by PIM1 kinase. Cardiac fibroblast (CF) population heterogeneity and plasticity present a challenge for categorization of biological and functional properties. Distinct molecular markers and associated signaling pathways provide valuable insight for CF biology and interventional strategies to influence injury response and aging-associated remodeling. Receptor tyrosine kinase c-Kit mediates cell survival, proliferation, migration, and is activated by pathological injury. However, the biological significance of c-Kit within CF population has not been addressed. The work presented in this dissertation demonstrated the phenotype of c-kit+ on CFs correlated with multiple characteristics of ‘youthful’ cells. This study provides a fundamental basis for future studies to influence myocardial biology, response to pathological injury and physiological aging.