title: High glucose suppresses embryonic stem cell differentiation into cardiomyocytes : High glucose inhibits ES cell cardiogenesis.
abstract: Babies born to mothers with pregestational diabetes have a high risk for congenital heart defects (CHD). Embryonic stem cells (ESCs) are excellent in vitro models for studying the effect of high glucose on cardiac lineage specification because ESCs can be differentiated into cardiomyocytes. ESC maintenance and differentiation are currently performed under high glucose conditions, whose adverse effects have never been clarified.
  
  
  
  We investigated the effect of high glucose on cardiomyocyte differentiation from a well-characterized ESC line, E14, derived from mouse blastocysts. E14 cells maintained under high glucose (25 mM) failed to generate any beating cardiomyocytes using the hanging-drop embryonic body method. We created a glucose-responsive E14 cell line (GR-E14) through a graduated low glucose adaptation. The expression of stem cell markers was similar in the parent E14 cells and the GR-E14 cells.
  
  
  
  Glucose transporter 2 gene was increased in GR-E14 cells. When GR-E14 cells were differentiated into cardiomyocytes under low (5 mM) or high (25 mM) glucose conditions, high glucose significantly delayed the appearance and reduced the number of TNNT2 (Troponin T Type 2)-positive contracting cardiomyocytes. High glucose suppressed the expression of precardiac mesoderm markers, cardiac transcription factors, mature cardiomyocyte markers, and potassium channel proteins. High glucose impaired the functionality of ESC-derived cardiomyocytes by suppressing the frequencies of Ca2+wave and contraction.
  
  
  
  Our findings suggest that high glucose inhibits ESC cardiogenesis by suppressing key developmental genes essential for the cardiac program.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, BRB11-039, 655W. Baltimore Street, Baltimore, MD, 21201, USA.
authors.forename: Penghua
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, BRB11-039, 655W. Baltimore Street, Baltimore, MD, 21201, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: Sunjay
authors.initials: S
authors.lastname: Kaushal
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, BRB11-039, 655W. Baltimore Street, Baltimore, MD, 21201, USA.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: E Albert
authors.initials: EA
authors.lastname: Reece
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, BRB11-039, 655W. Baltimore Street, Baltimore, MD, 21201, USA. pyang@fpi.umaryland.edu.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. pyang@fpi.umaryland.edu.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D038081:Organogenesis / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014157:Transcription Factors; D005947:Glucose
keywords: Cardiogenesis; Contracting cardiomyocytes; Embryonic stem cells; High glucose