title: Improvement of cardiac function in mouse myocardial infarction after transplantation of epigenetically-modified bone marrow progenitor cells.
abstract: OBJECTIVE
  To study usefulness of bone marrow progenitor cells (BPCs) epigenetically altered by chromatin modifying agents in mediating heart repair after myocardial infarction in mice.
  
  
  RESULTS
  We tested the therapeutic efficacy of bone marrow progenitor cells treated with the clinically-used chromatin modifying agents Trichostatin A (TSA, histone deacetylase inhibitor) and 5Aza-2-deoxycytidine (Aza, DNA methylation inhibitor) in a mouse model of acute myocardial infarction (AMI). Treatment of BPCs with Aza and TSA induced expression of pluripotent genes Oct4, Nanog, Sox2, and thereafter culturing these cells in defined cardiac myocyte-conditioned medium resulted in their differentiation into cardiomyocyte progenitors and subsequently into cardiac myocytes. Their transition was deduced by expression of repertoire of markers: Nkx2.5, GATA4, cardiotroponin T, cardiotroponin I, α-sarcomeric actinin, Mef2c and MHC-α. We observed that the modified BPCs had greater AceH3K9 expression and reduced histone deacetylase1 (HDAC1) and lysine-specific demethylase1 (LSD1) expression compared to untreated BPCs, characteristic of epigenetic changes. Intra-myocardial injection of modified BPCs after AMI in mice significantly improved left ventricular function. These changes were ascribed to differentiation of the injected cells into cardiomyocytes and endothelial cells.
  
  
  CONCLUSIONS
  Treatment of BPCs with Aza and TSA converts BPCs into multipotent cells, which can then be differentiated into myocyte progenitors. Transplantation of these modified progenitor cells into infarcted mouse hearts improved left ventricular function secondary to differentiation of cells in the niche into myocytes and endothelial cells.
authors.affiliation: Department of Pharmacology and Center of Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, United States of America. rjohnson9@kumc.edu
authors.forename: Johnson
authors.initials: J
authors.lastname: Rajasingh
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Thangavel
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Siddiqui
authors.forename: Ignatius
authors.initials: I
authors.lastname: Gomes
authors.forename: Xiao-pei
authors.initials: XP
authors.lastname: Gao
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects; D000077209:Decitabine; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000503:physiopathology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000601:surgery
chemical_list: D006877:Hydroxamic Acids; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine