Abstract 1820: Derivation of Multipotent Stem Cells from Epigenetically Modified Endothelial Progenitor Cells
Endothelial progenitor cells (EPC) have been repeatedly shown to induce neo-vascularization in the ischemic myocardium and are being used in a number of ongoing clinical trials. Trans-differentiation of EPCs to other cell lineages like cardiomyocytes is, however, not well established. Since the goal of myocardial cell therapies is also to replace lost myocytes, generation of multi-potent stem cells from EPCs may provide an attractive source of cells for cardiac regenerative medicine. We tested the hypothesis that the treatment of EPC with chromatin modifying agents Trichostain A (histone deacetylase 1 inhibitor) and 5Aza-2-deoxycytidine (DNA methylation inhibitor) may induce epigenetic modifications leading to re-expression of pluripotency associated genes. We report that treatment of EPC with TSA+5Aza induces the expression of pluripotency associated genes Oct4, Nanog and SOX2 while down-regulating EPC specific gene expression. Methylation analysis of Oct4 promoter revealed that treated EPCs show a higher degree of CpG demethylation in Oct4 promoter. Additionally, chromatin immunoprecipitation (ChIP) experiments revealed increased Histone 3 acetylation at lysine (K) 4 (H3-K4) and reduced H3-K9 methylation in the oct4 promoter. Under specific culture conditions, treated EPCs showed effective trans-differentiation into cardiomyocytes and neuronal cells while untreated EPCs did not Taken together our biochemical and molecular data provide evidence that epigenetic reprogramming of EPCs generate a subset of cells that can trans-differentiate into multiple cell types, in vitro. A better understanding of molecular switching governing these changes may in future identify mechanisms/molecules to generate embryonic stem like cells from autologous EPCs for application in regenerative medicine.