title: Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes.
abstract: OBJECTIVE
  The differentiation of embryonic stem (ES) cells into energetically efficient cardiomyocytes contributes to functional cardiac repair and is envisioned to ameliorate progressive degenerative cardiac diseases. Advanced cell maturation strategies are therefore needed to create abundant mature cardiomyocytes. In this study, we tested whether the redox-sensitive heme oxygenase-1/carbon monoxide (HO-1/CO) system, operating through mitochondrial biogenesis, acts as a mechanism for ES cell differentiation and cardiomyocyte maturation.
  
  
  RESULTS
  Manipulation of HO-1/CO to enhance mitochondrial biogenesis demonstrates a direct pathway to ES cell differentiation and maturation into beating cardiomyocytes that express adult structural markers. Targeted HO-1/CO interventions up- and downregulate specific cardiogenic transcription factors, transcription factor Gata4, homeobox protein Nkx-2.5, heart- and neural crest derivatives-expressed protein 1, and MEF2C. HO-1/CO overexpression increases cardiac gene expression for myosin regulatory light chain 2, atrial isoform, MLC2v, ANP, MHC-β, and sarcomere α-actinin and the major mitochondrial fusion regulators, mitofusin 2 and MICOS complex subunit Mic60. This promotes structural mitochondrial network expansion and maturation, thereby supporting energy provision for beating embryoid bodies. These effects are prevented by silencing HO-1 and by mitochondrial reactive oxygen species scavenging, while disruption of mitochondrial biogenesis and mitochondrial DNA depletion by loss of mitochondrial transcription factor A compromise infrastructure. This leads to failure of cardiomyocyte differentiation and maturation and contractile dysfunction.
  
  
  METHODS
  The capacity to augment cardiomyogenesis via a defined mitochondrial pathway has unique therapeutic potential for targeting ES cell maturation in cardiac disease.
  
  
  CONCLUSIONS
  Our findings establish the HO-1/CO system and redox regulation of mitochondrial biogenesis as essential factors in ES cell differentiation as well as in the subsequent maturation of these cells into functional cardiac cells.
authors.affiliation: 1 Department of Medicine, Duke University School of Medicine , Durham, North Carolina.|2 Department of Anesthesiology, Duke University School of Medicine , Durham, North Carolina.|3 Department of Pathology, Duke University School of Medicine , Durham, North Carolina.
authors.forename: Hagir B
authors.initials: HB
authors.lastname: Suliman
authors.affiliation: 4 Department of Chemistry, University of Fribourg , Fribourg, Switzerland .
authors.forename: Fabio
authors.initials: F
authors.lastname: Zobi
authors.affiliation: 1 Department of Medicine, Duke University School of Medicine , Durham, North Carolina.|2 Department of Anesthesiology, Duke University School of Medicine , Durham, North Carolina.|3 Department of Pathology, Duke University School of Medicine , Durham, North Carolina.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D000066673:Cell Self Renewal / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D050814:Octamer Transcription Factor-3; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors; C081930:Tfam protein, mouse; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1