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.

来自人类胚胎干细胞 (hESC-CMs) 和诱导多能干细胞 (hiPSC-CMs) 的心肌细胞代表了药物发现的新模型。尽管肥大是一个高度优先的目标，但我们发现与 hESC-CM 相比，hiPSC-CM 对肥大信号（例如 α-肾上腺素受体 (αAR) 激动剂苯肾上腺素 (PE)）系统性无反应。我们研究了多个级别的信号，以了解这种差异反应的潜在机制。正常 α ₁ AR 基因ADRA1A的表达在分化过程中可逆地沉默，伴随着ADRA1B任何一种细胞类型的上调。ADRA1B 信号在 hESC-CMs 中是完整的，但在 hiPSC-CMs 中不是。我们观察到 hiPSC-CM 中抑制性激酶通路的强直活性增加，并且抗肥大激酶的抑制显示肥大性增加。在 hiPSC-CM 中存在对细胞生长的强直抑制，但在 hESC-CM 中没有，限制了它们在肥大信号研究中的使用。这些数据提出了关于 hiPSC-CM 作为心脏病某些方面的有效模型的问题。