Trichostatin A enhances vascular repair by injected human endothelial progenitors through increasing the expression of TAL1-dependent genes

Cell Stem Cell. 2014 May 1;14(5):644-57. doi: 10.1016/j.stem.2014.03.003.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Endothelial Progenitor Cells / cytology
  • Endothelial Progenitor Cells / drug effects*
  • Endothelial Progenitor Cells / metabolism*
  • Epigenesis, Genetic / genetics
  • Genome-Wide Association Study
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • T-Cell Acute Lymphocytic Leukemia Protein 1

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hydroxamic Acids
  • Proto-Oncogene Proteins
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • TAL1 protein, human
  • trichostatin A

Associated data

  • GEO/GSE44442
  • GEO/GSE44444
  • GEO/GSE44546
  • GEO/GSE53423