MESENCHYMAL STEM CELL THERAPEUTICS IN HIBERNATING MYOCARDIUM
LEE, TECHUNG Principal Investigator
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Chronic myocardial ischemia leading to heart failure is a leading cause of morbidity and mortality in theUnited States. Experimental myocardial stem cell therapeutics have been performed largely in the acuteischemia model. The well established porcine hibernating myocardium model, which closely resembles thechronicity and stability of human coronary artery disease, will be used to develop and optimize therapeuticstrategies based on combined stem cell and gene therapy. Bone marrow-derived porcine mesenchymalstem cells (MSCs) expanded in culture possess robust self-renewal and multilineage differentiationpotentials, and are capable of producing many growth factors and cytokines. Although promising asregenerative medicine in aging and disease, MSCs await further analysis regarding the mechanismsgoverning their growth, differentiation, survival, tissue homing, and aging characteristics. Growth factormodulation of MSC multilineage potential, the influence of aging on the function of MSCs, and the use ofallogeneic MSCs will be characterized. Central to these efforts is the use of recombinant adenovirusexpressing genes involved in cytoprotection, angiogenesis, and MSC homing. The first part of the proposalrelies on extensive cell culture characterizations of MSCs, building the foundation for the second part of theproposal that addresses the physiological effect of engineered MSCs. Aim 1 will determine the differentialeffects of multiple VEGF isoforms on the growth and multilineage potentials of porcine MSCs. Aim 2 willanalyze the expression and regulation of MSC chemokine receptors involved in myocardial MSC homing.Aim 3 will characterize the influence of cellular and animal aging on MSC growth capability, cell survivalcapacity, multilineage potential, and chemotactic migratory potency. Aim 4 will optimize strategies fortracking and identifying the in vivo fate of implanted MSCs in the myocardium and evaluate the feasibility ofusing allogeneic and aged MSCs. Aim 5 will determine whether MSCs engineered for enhanced survivalcapacity, angiogenic potential, or homing potency can better improve flow and function in chronichibernating myocardium. Long term, the translation between the MSC-based therapy in the porcinehibernating myocardium and regenerative medicine for humans with chronic coronary artery disease will lead to optimized MSC therapeutics that can be of clinical value in managing aging and curing disease.