title: The Epigenetic Regulator HDAC1 Modulates Transcription of a Core Cardiogenic Program in Human Cardiac Mesenchymal Stromal Cells Through a p53-Dependent Mechanism.
abstract: Histone deacetylase (HDAC) regulation is an essential process in myogenic differentiation. Inhibitors targeting the activity of specific HDAC family members have been shown to enhance the cardiogenic differentiation capacity of discrete progenitor cell types; a key property of donor cell populations contributing to their afforded benefits in cardiac cell therapy applications. The influence of HDAC inhibition on cardiac-derived mesenchymal stromal cell (CMC) transdifferentiation or the role of specific HDAC family members in dictating cardiovascular cell lineage specification has not been investigated. In the current study, the consequences of HDAC inhibition on patient-derived CMC proliferation, cardiogenic program activation, and cardiovascular differentiation/cell lineage specification were investigated using pharmacologic and genetic targeting approaches. Here, CMCs exposed to the pan-HDAC inhibitor sodium butyrate exhibited induction of a cardiogenic transcriptional program and heightened expression of myocyte and endothelial lineage-specific markers when coaxed to differentiate in vitro. Further, shRNA knockdown screens revealed CMCs depleted of HDAC1 to promote the induction of a cardiogenic transcriptional program characterized by enhanced expression of cardiomyogenic- and vasculogenic-specific markers, a finding which depended on and correlated with enhanced acetylation and stabilization of p53. Cardiogenic gene activation and elevated p53 expression levels observed in HDAC1-depleted CMCs were associated with improved aptitude to assume a cardiomyogenic/vasculogenic cell-like fate in vitro. These results suggest that HDAC1 depletion-induced p53 expression alters CMC cell fate decisions and identify HDAC1 as a potential exploitable target to facilitate CMC-mediated myocardial repair in ischemic cardiomyopathy. Stem Cells 2016;34:2916-2929.
authors: Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors: Joseph B
authors: JB
authors: Moore
authors: Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors: John
authors: J
authors: Zhao
authors: Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors: Matthew C L
authors: MC
authors: Keith
authors: Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors: Alok R
authors: AR
authors: Amraotkar
authors: Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors: Marcin
authors: M
authors: Wysoczynski
authors: Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors: Kyung U
authors: KU
authors: Hong
authors: Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
authors: Roberto
authors: R
authors: Bolli
mesh_terms: D000107:Acetylation; D015415:Biomarkers / Q000378:metabolism; D020148:Butyric Acid / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016159:Tumor Suppressor Protein p53; D020148:Butyric Acid; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: Cardiac mesenchymal stromal cells; Cardiogenic differentiation; Cardiogenic gene expression; Histone deacetylase inhibitors; Histone deacetylases; Vasculogenic differentiation; p53