Epigenomic Memory of iPSC-Derived Endothelial Cells for Cardiovascular Diseases

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DESCRIPTION (provided by applicant): Induced pluripotent stem cells (iPSCs) are a novel source for cardiovascular regenerative medicine. Because iPSCs are derived from the tissues of recipient patients, they obviate two major problems in the field of human embryonic stem cells (hESCs), namely immune rejection and the political/ethical concerns regarding the destruction of embryos. However, at present the field is in its infancy, and issues surrounding the efficiency, safety, and efficacy of iPSC-based derivatives require resolution before reduction to clinical practice occurs. This multi-disciplinary project will investigate the epigenomics of iPSC-derived endothelial cells (iPSC-ECs) for use in a murine myocardial infarction model. First, endothelial cells and fibroblasts will be de-differentiated into iPSCs. These two lines, as well as hESCs, will then be differentiating into endothelial cells. The stem cells, their tissues of origin (for the two iPSCs), and their endothelial derived tissues will be subjected to second-generation sequencing to determine their epigenomic states. Finally, the three stem cell-derived endothelial cell lines will be injected into a murine myocardial infarction system. Their effects on myocardial function will be observed over time. These experiments are anticipated to reveal the epigenomic features underlying more efficient somatic cell reprogramming, more robust stem cell differentiation, and greater therapeutic capacity for myocardial ischemia. These studies should pave the way to identifying molecular interventions which can be integrated into iPSC-EC preparation, so that eventually, these stem cell derivatives may be effective in the clinical setting for cardiovascular disease patients