Reprogramming of Endothelial Progenitor Cells: Unipotency Towards Multipotency

Abstract

The development of autologous stem cells with enhanced lineage plasticity for subsequent testing in myocardial ischemia is an integral part of stem‐cell research. We tested the hypothesis that the treatment of EPC with chromatin modifying agents Trichostatin A (TSA‐ inhibitor for histone deacetylase) and 5Aza‐2‐deoxycytidine (5Aza‐ inhibitor for DNA methylation) influence histone acetylation and DNA methylation respectively thereby modify the chromatin structure and up‐regulates embryonic stem gene expression. In a series of preliminary experiments performed with EPCs that had been treated with 5Aza and TSA, we made the following observations: 1) 5Aza and TSA treatment induced expression of pluripotent genes (Oct4 and Nanog), cardiac stem cell marker Flk1 and down regulated expression of endothelial‐specific genes, 2) treated EPCs differentiated into ectodermal (neuronal) and mesodermal (cardiomyocyte) lineages, 3) aceH3K9 activity was higher and HDAC1 activity was lower in treated EPCs than in control cells, 4) functional and histological evidence from our preliminary studies in mouse AMI model also suggest that intracardiac transplantation of reprogrammed EPC improve left ventricular functions and differentiate into cardiomyocytes and endothelial cell phenotypes. Thus, the epigenetic modifying agents can de‐differentiate EPCs into cells with a more multipotent phenotype, and the de‐differentiated EPCs can subsequently differentiate into multiple cell lineages, including cardiomyocytes that could be used as potential source of cells for treating degenerative diseases.Grant Funding Source: NHLBI