期刊
STEM CELL REPORTS
卷 3, 期 5, 页码 905-914出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2014.09.002
关键词
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资金
- Foundation Leducq
- British Heart Foundation
- Medical Research Council
- Marie Curie Reintegration (FP7) [ndegreesPIRG08-GA-2010-276811]
- OTKA [105555, K100638]
- BBSRC [BB/E006159/1] Funding Source: UKRI
- MRC [G0801098, MR/L012618/1, MC_EX_G0800785, G113/30] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E006159/1] Funding Source: researchfish
- British Heart Foundation [PG/09/027/27141, RG/11/19/29264, RG/14/1/30588] Funding Source: researchfish
- Medical Research Council [G113/30, MR/L012618/1, MC_EX_G0800785, G0801098] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/C013105/1, G1000035/1, NC/K000225/1] Funding Source: researchfish
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 alpha-adrenoceptor (alpha AR) 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 alpha(1)AR 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.
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