title: 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.
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada.
authors.forename: Carmen G
authors.initials: CG
authors.lastname: Palii
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: Branka
authors.initials: B
authors.lastname: Vulesevic
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fraineau
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: Erinija
authors.initials: E
authors.lastname: Pranckeviciene
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Ottawa-Carleton Joint Program in Biomedical Engineering, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Griffith
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada.
authors.forename: Alphonse
authors.initials: A
authors.lastname: Chu
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: Hervé
authors.initials: H
authors.lastname: Faralli
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: McNeill
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Ottawa-Carleton Joint Program in Biomedical Engineering, University of Ottawa, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Perkins
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: F Jeffrey
authors.initials: FJ
authors.lastname: Dilworth
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Perez-Iratxeta
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Allan
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H8L6, Canada. Electronic address: mbrand@ohri.ca.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Brand
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C067143:TAL1 protein, human; C012589:trichostatin A