Inhibition of DNA methyltransferases and histone deacetylases induces bone marrow-derived multipotent adult progenitor cells to differentiate into endothelial cells.
Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular diseases and cancer. Bone marrow-derived multipotent adult progenitor cells (MAPC) have the potential to differentiate, at the single cell level, toward the three embryonic germ layers and may be the progenitors of the other tissue-specific stem cells. However, molecular mechanisms of endothelial differentiation from MAPC have not been defined. The importance of epigenetic changes such as DNA methylation and histone acetylation in gene regulatory networks during embryonic stem cell (ESC) differentiation has been documented. We postulated that endothelial cell (EC) differentiation from MAPC could be enhanced by inhibiting DNA methylation and histone deacetylation, reversing the repression of genes that specify EC fate.



MAPCs were derived from rat bone marrow and differentiated into EC by vascular endothelial growth factor (VEGF) treatment in the presence or absence of the specific DNA methyltransferase (DNMT) inhibitor 5'-aza-2'-deoxycytidine (aza-dC) and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Expression of the endothelial marker genes was assessed by real time quantitative PCR and angiogenic potential of the differentiated EC was assessed by analysis of vascular network formation on fibronectin.



Both aza-dC and TSA induced at least a three-fold increase in the expression of the EC marker genes VE-cadherin, vWF, and Flk1. This increase was also observed in the presence of the EC differentiation inducer VEGF, suggesting that factors other than VEGF mediate the response to the epigenetic agents. Both DNMT and HDAC inhibition stimulated vascular network formation.



Epigenetic therapy holds a potential in inducing self-repair, vascular tissue regeneration, controlling angiogenesis and endothelial dysfunction.
Mahapatra
Saswati
S
Department of Medicine, Division of Endocrinology and Stem Cell Institute, University of Minnesota, Minneapolis, USA.
Firpo
Meri T
MT
Bacanamwo
Methode
M
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D039902:Multipotent Stem Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D056572:Histone Deacetylase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D004248:DNA (Cytosine-5-)-Methyltransferases