Journal article

Heme oxygenase-1/carbon monoxide system and embryonic stem cell differentiation and maturation into cardiomyocytes

  • Suliman, Hagir B. Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA - Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA - Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
  • Zobi, Fabio Department of Chemistry, University of Fribourg, Switzerland
  • Piantadosi, Claude A. Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA - Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA - Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
    04.01.2016
Published in:
  • Antioxidants & Redox Signaling. - 2016, vol. 24, no. 7, p. 345–360
English 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. Innovation: The capacity to augment cardiomyogenesis via a defined mitochondrial pathway has unique therapeutic potential for targeting ES cell maturation in cardiac disease. Conclusion: 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.
Faculty
Faculté des sciences et de médecine
Department
Département de Chimie
Language
  • English
Classification
Chemistry
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/304946
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