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Aberrant α-Adrenergic Hypertrophic Response in Cardiomyocytes from Human Induced Pluripotent Cells

Földes, G; Matsa, E; Kriston-Vizi, J; Leja, T; Amisten, S; Kolker, L; Kodagoda, T; ... Harding, SE; + view all (2014) Aberrant α-Adrenergic Hypertrophic Response in Cardiomyocytes from Human Induced Pluripotent Cells. Stem Cell Reports , 3 (5) 905- 914. 10.1016/j.stemcr.2014.09.002. Green open access

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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 αAR 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. In this article, Fo¨ldes and colleagues show that hiPSC-derived cardiomyocytes are relatively unresponsive to α-adrenergic hypertrophic signals compared to hESC cardiomyocytes. The main difference in hiPSC-CMs that accounts for the defective response is the suppression of growth by tonic antihypertrophic pathways. Superficial similarities in phenotype between cardiomyocytes derived from hESCs or hiPSCs may mask complex differences in signaling.

Type: Article
Title: Aberrant α-Adrenergic Hypertrophic Response in Cardiomyocytes from Human Induced Pluripotent Cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.stemcr.2014.09.002
Publisher version: http://dx.doi.org/10.1016/j.stemcr.2014.09.002
Language: English
Additional information: This work is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivativeWorks 3.0 license. You are free to share (copy, distribute and transmit the work), but you must attribute the author, you may not use this work for commercial purposes and you may not alter, transform, or build upon this work and distribute any derivative works you create under a similar license. http://creativecommons.org/licenses/by-nc-nd/3.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1456503
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