DESCRIPTION (provided by applicant): Ischemic heart disease is the leading cause of congestive heart failure. The ultimate therapy would pursue stem cell-based regeneration. Bone marrow (BM) can be regarded as the major reservoir of stem cells. Stromal-derived factor-11 (SDF-11) induced by myocardial ischemia plays a critical role for recruiting circulating BM-derived stem cells (BMSC) to ischemia myocardium for heart repair via binding of SDF-1 to CXC chemokine receptor 4 (CXCR4). Besides exogenous stem cells, compelling evidence has accumulated suggesting that the heart has endogenous regenerative potential. Resident cardiac stem cells (CSCs) are potentially available for self-renewing of adult heart. However, myocardial damage from ischemia is usually irreversible. Proposed mechanisms for the failure of endogenous heart repair include: acute depletion of resident CSCs after myocardial infarction (MI), inadequate proliferation and self-renewal of CSCs to rapidly reconstitute CSC population in heart, and limited and transient endogenous homing signals (e.g. SDF-11) induced by myocardial ischemia. We propose to replenish the stem cell pool for heart repair, by isolating and expanding CSCs from heart in vitro, infusing them systemically back in vivo post MI, and recruiting them to the ischemic myocardium using SDF-11/CXCR4 signal pathway. However, major challenges remain, including low level of CXCR4 expression of CSCs under normal conditions, the poor survival of grafted cells, which has limited the reparative capacity of stem cells in vivo. We propose a series of in vitro experiments and in vivo experiments to verify that hypoxia preconditioning can be utilized to increase CSC homing via regulation of CXCR4 expression and enhance survival of homed cells via cytoprotection in acute ischemic myocardium. In addition, recombinant adeno-associated virus (rAAV) mediated SDF-1 gene therapy may permit us to conduct CSC transplantation for patients with chronic myocardial ischemia. To test these hypotheses, we propose the following Specific Aims: (1) To evaluate hypoxia induced cardiac stem cell homing: role of CXCR4 and HIF-11 in cell recruitment and retention. (2) To determine whether hypoxia-preconditioning can enhance homed CSC survival and characterize the mechanism. (3) To investigate the possibility of homing CSC to chronic ischemia myocardium via rAAV virus mediated SDF-11 gene therapy.
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