Article

Original Research Enhanced Angiogenic and Cardiomyocyte Differentiation Capacity of Epigenetically Reprogrammed Mouse and Human Endothelial Progenitor Cells Augments Their Efficacy for Ischemic Myocardial Repair

Circulation Research (Impact Factor: 11.86). 01/2012;

ABSTRACT Rationale: Although bone marrow endothelial progenitor cell (EPC)-based therapies improve the symptoms in patients with ischemic heart disease, their limited plasticity and decreased function in patients with existing heart disease limit the full benefit of EPC therapy for cardiac regenerative medicine. Objective: We hypothesized that reprogramming mouse or human EPCs, or both, using small molecules targeting key epigenetic repressive marks would lead to a global increase in active gene transcription, induce their cardiomyogenic potential, and enhance their inherent angiogenic potential. Method and Results: Mouse Lin-Sca1 CD31 EPCs and human CD34 cells were treated with inhibitors of DNA methyltransferases (5-Azacytidine), histone deacetylases (valproic acid), and G9a histone dimethyl-transferase. A 48-hour treatment led to global increase in active transcriptome, including the reactivation of pluripotency-associated and cardiomyocyte-specific mRNA expression, whereas endothelial cell–specific genes were significantly upregulated. When cultured under appropriate differentiation conditions, repro-grammed EPCs showed efficient differentiation into cardiomyocyte and vascular smooth muscle cells. Treatment with epigenetic-modifying agents show marked increase in histone acetylation on cardiomyocyte and pluripotent cell–specific gene promoters. Intramyocardial transplantation of reprogrammed mouse and human EPCs in an acute myocardial infarction mouse model showed significant improvement in ventricular functions, which was histologically supported by their de novo cardiomyocyte differentiation and increased capillary density and reduced fibrosis. Importantly, cell transplantation was safe and did not form teratomas. Conclusions: Taken together, our results suggest that epigenetically reprogrammed EPCs display a safe, more plastic phenotype and improve postinfarct cardiac repair by both neocardiomyogenesis and neovascularization. (Circ Res. 2012;111:00-00.) Key Words: cardiomyogenesis cell therapy endothelial progenitor cell epigenetic modification histone acetylation myocardial ischemia transdifferentiation D espite the pervasive belief that the heart has limited regenerative capacity, progenitor cell– based therapy has been shown to provide substantial clinical benefits for ische-mic diseases such as chronic angina, acute myocardial infarc-tion (AMI), and heart failure. 1– 6 Specifically, murine endo-thelial progenitor cells (EPCs) 7 and the human equivalent CD34 mononuclear cells are capable of homing to infarct and peri-infarct myocardium on ischemia, inducing angiogen-esis/vasculogenesis, and augmenting cardiac function and survival through paracrine-mediated growth factor secre-tion. 8 –10 Although the revascularization appears to result in real improvements in quality of life, the ultimate goal of cardiovascular regenerative medicine is to regenerate lost myocytes in addition to neovasculature. There is no convinc-ing evidence that EPCs have cardiomyocyte differentiation potential. 11,12 Also, because the EPCs from aged patients with existing metabolic diseases and cardiovascular risk factors are known to have diminished functional properties,

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