National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; Heart and Vascular Center, Semmelweis University, Budapest H1122, Hungary.
Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
Stem Cell Reports. 2014 Nov 11;3(5):905-14. doi: 10.1016/j.stemcr.2014.09.002. Epub 2014 Oct 11.
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.
人类胚胎干细胞（hESC-CMs）和诱导多能干细胞（hiPSC-CMs）来源的心肌细胞代表了药物发现的新模型。尽管肥大是一个优先考虑的目标，但我们发现与 hESC-CMs 相比，hiPSC-CMs 对肥大信号（如 α-肾上腺素受体（αAR）激动剂苯肾上腺素（PE））的反应系统地不敏感。我们在多个层面上研究了信号转导，以了解这种差异反应的潜在机制。在分化过程中，正常的 α1AR 基因 ADRA1A 的表达可被可逆沉默，而两种细胞类型中 ADRA1B 的表达上调。hESC-CMs 中 ADRA1B 信号转导完整，但 hiPSC-CMs 中没有。我们观察到 hiPSC-CMs 中抑制性激酶途径的紧张性活性增加，而抗肥大激酶的抑制揭示了肥大的增加。hiPSC-CMs 中存在细胞生长的紧张性抑制，但 hESC-CMs 中没有，这限制了它们在肥大信号转导研究中的应用。这些数据提出了关于 hiPSC-CM 是否可以作为心脏疾病某些方面的有效模型的问题。
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