title: Aberrant α-adrenergic hypertrophic response in cardiomyocytes from human induced pluripotent cells.
abstract: Cardiomyocytes from human embryonic stem cells (hESC-CMs) and induced pluripotent stem cells (hiPSC-CMs) represent new models for drug discovery. Although hypertrophy is a high-priority target, we found that hiPSC-CMs were systematically unresponsive to hypertrophic signals such as the α-adrenoceptor (αAR) agonist phenylephrine (PE) compared to hESC-CMs. We investigated signaling at multiple levels to understand the underlying mechanism of this differential responsiveness. The expression of the normal α1AR gene, ADRA1A, was reversibly silenced during differentiation, accompanied by ADRA1B upregulation in either cell type. ADRA1B signaling was intact in hESC-CMs, but not in hiPSC-CMs. We observed an increased tonic activity of inhibitory kinase pathways in hiPSC-CMs, and inhibition of antihypertrophic kinases revealed hypertrophic increases. There is tonic suppression of cell growth in hiPSC-CMs, but not hESC-CMs, limiting their use in investigation of hypertrophic signaling. These data raise questions regarding the hiPSC-CM as a valid model for certain aspects of cardiac disease.
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; Heart and Vascular Center, Semmelweis University, Budapest H1122, Hungary. Electronic address: g.foldes@imperial.ac.uk.
authors.forename: Gabor
authors.initials: G
authors.lastname: Földes
authors.affiliation: Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Matsa
authors.affiliation: Bioinformatics Image Core, Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: János
authors.initials: J
authors.lastname: Kriston-Vizi
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Leja
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism, Oxford University, The Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Amisten
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; National Institute for Biological Standards and Controls, Cell Biology and Imaging, Hertfordshire EN6 3QG, UK.
authors.forename: Ljudmila
authors.initials: L
authors.lastname: Kolker
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Thusharika
authors.initials: T
authors.lastname: Kodagoda
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Nazanin F
authors.initials: NF
authors.lastname: Dolatshad
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Mioulane
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Karine
authors.initials: K
authors.lastname: Vauchez
authors.affiliation: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest H1113, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Arányi
authors.affiliation: Bioinformatics Image Core, Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Ketteler
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Denning
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006984:Hypertrophy; D007093:Imidazoles / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C547713:ADRA1A protein, human; C547716:ADRA1B protein, human; D018663:Adrenergic Agents; D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; C049763:CGP 20712A; D007545:Isoproterenol