Trichostatin A Enhances Vascular Repair by Injected Human Endothelial Progenitors through Increasing the Expression of TAL1-Dependent Genes

Abstract

A major goal of cell therapy for vascular diseases is to promote revascularization through the injection of endothelial stem/progenitor cells. The gene regulatory mechanisms that underlie endothelial progenitor-mediated vascular repair, however, remain elusive. Here, we identify the transcription factor TAL1/SCL as a key mediator of the vascular repair function of primary human endothelial colony-forming cells (ECFCs). Genome-wide analyses in ECFCs demonstrate that TAL1 activates a transcriptional program that promotes cell adhesion and migration. At the mechanistic level, we show that TAL1 upregulates the expression of migratory and adhesion genes through recruitment of the histone acetyltransferase p300. Based on these findings, we establish a strategy that enhances the revascularization efficiency of ECFCs after ischemia through ex vivo priming with the histone deacetylase inhibitor TSA. Thus, small molecule epigenetics drugs are effective tools for modifying the epigenome of stem/progenitor cells prior to transplantation as a means to enhance their therapeutic potential.

CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect

“…ECFCs can be isolated from human cord or peripheral blood and have robust clonal proliferative potential. They have been reported to home to the site of tissue ischemia after intravenous injection, where they improve circulation in a model of myocardial infarction (4), stroke (5), ischemic retinopathy (6,7), and ischemic limb injury (8,9). Although a paracrine trophic rescue effect of ECFCs has been postulated (10,11), factors that may mediate this effect remain poorly characterized.…”

SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells

“…TSA has been shown to successfully improve cardiomyocyte differentiation protocols of human pluripotent cell lines. 42 In addition, very recently, Palii et al 43 have demonstrated that ex vivo TSA administration of primary human endothelial colony-forming cells enhanced revascularization after ischemia in a mouse model through the upregulation of a set of SCL-dependent genes. In accordance with Connectivity Map prediction, Vulcano et al 44 showed that VPA, which is another HDAC inhibitor, induced the expression of CD41 and CD61 in the megakaryoblastic leukemia cell line UT-7.…”

Regenerative Therapy and Immune Modulation Using Umbilical Cord Blood–Derived Cells

“…EPC-like cells and angiogenic cells are often impaired in patients with vascular disease, such as coronary artery disease, and in patients with diabetes, and strategies to augment the function of these cells have been addressed by several groups, building on insight regarding key mechanisms of action. We recently reported on the importance of TAL1 Q 6 as a central transcription factor that regulates a complex gene network implicated in migration, adhesion, and tubule-forming functions of ECFC [49]. Moreover, TAL1 colocalizes with enzymes such as p300 (a histone acetylase) and various histone deacetylases and demethylases, underscoring the importance of epigenetic histone modification in the control of gene expression networks in ECFCs.…”