Abstract 13139: In vivo Differentiation of Epigenetically Reprogrammed Mouse and Human Endothelial Progenitor Cells Into Cardiomyocytes Enhances Functional and Anatomical Post-Infarct Myocardial Repair
Background: Currently, bone marrow derived endothelial progenitor cells (EPCs) are being used clinically to improve vascularization in patients with ischemic heart disease. While it is generally accepted that EPCs participate in vascular repair of the ischemic myocardium, there exists no convincing evidence that these cells are capable of trans-differentiating into functional cardiomyocytes (CMC). Since ischemic heart disease leads to substantial loss of CMC, cardiomyogenic plasticity of an existing autologous cell therapy is of obvious import. EPCs and CMC both differentiate from a common mesodermal progenitor cell however; during specific lineage differentiation to EC phenotype CMC specific genes are epigenetically silenced. We hypothesized that reprogramming of EPC using small molecules targeting key epigenetic repressive marks may recapitulate cardiomyogenic potential in EPCs.
Method and Results: Mouse Lin-Sca1+CD31+ BM cells (EPCs) were sorted and treated with inhibitors of DNA methyltransferases (5-Azacytidine), histone deacetylases (valproic acid) and G9a histone methyltransferase. Forty-eight hour treatment led to the reactivation of pluripotency associated and CMC specific mRNA expression while EC specific gene expression was maintained or enhanced. When cultured under appropriate differentiation conditions, reprogrammed EPCs showed efficient differentiation into CMC. Epigenetically, treatment of EPCs showed significant hyper acetylation of Histone 3 lysine 9 (H3-K9) and multiple H4 lysine residues. Intra-myocardial transplantation of reprogrammed eGFP-EPCs in an acute myocardial infarction mouse model showed significant improvement in LV functions compared to control EPCs and this was histologically supported by the de novo CMC differentiation (GFP+sarcomeric actinin double positive) as well as increased capillary density and significantly reduced fibrosis. Similar findings were recapitulated with the human CD34+ EPC population in AMI model using immuno-deficient mice.
Conclusions: Taken together, our results suggest that epigenetically reprogrammed EPCs display a more plastic phenotype and improve post-infarct cardiac repair by both neo-cardiomyogenesis and neovascularization.
- © 2011 by American Heart Association, Inc.