心脏特异性离子通道在人胚胎干细胞衍生的心肌细胞中的功能表达和药物功效。,Scientific Reports

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心脏特异性离子通道在人胚胎干细胞衍生的心肌细胞中的功能表达和药物功效。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Oct-23 , DOI: 10.1038/s41598-017-14198-y
Han Sol Kim , Jung Won Yoon , Hongliang Li , Geun Ok Jeong , Jin Ju Park , Sung Eun Shin , Il Ho Jang , Jae Ho Kim , Won Sun Park

从人多能干细胞分化出来的心肌细胞为筛选心脏毒性药物提供了有前途的工具。为了评估人多能干细胞衍生的心肌细胞的心脏毒性测试，在本研究中，将人胚胎干细胞（hESCs）分化为心肌细胞，然后进行代谢选择以富集分化的心肌细胞。高度纯化的源自hESC的心肌细胞（hESC-CM）表达了几种心肌细胞特异性标记物，包括cTnT，MLC2a和α-SA，但没有多能性标记物，例如OCT4和NANOG。膜片钳技术和RT-PCR揭示了心肌细胞特异性Na ⁺，Ca ²⁺和K ^+的表达hESC-CMs中的通道和心脏动作电位。为了探索将hESC-CMs用作功能性心肌细胞进行药物发现和心脏毒性筛查的潜在用途，我们研究了抑制天然心脏Ca ²⁺通道的bisindolylmaleimide（BIM）（I）对hESC的Ca ²⁺通道活性的影响。 -CM。我们观察到了类似的响应，即BIM（I）通过L型Ca ²⁺通道电流对hESC-CM和天然心肌细胞之间的Ca ²⁺通道进行了调节。这些结果表明，hESC-CMs可用于评估心脏研究中新药候选者的药效和安全性。

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Functional expression and pharmaceutical efficacy of cardiac-specific ion channels in human embryonic stem cell-derived cardiomyocytes.

Cardiomyocytes differentiated from human pluripotent stem cells provide promising tools for screening of cardiotoxic drugs. For evaluation of human pluripotent stem cell-derived cardiomyocytes for cardiotoxicity test, in the present study, human embryonic stem cells (hESCs) were differentiated to cardiomyocytes, followed by metabolic selection to enrich the differentiated cardiomyocytes. The highly purified hESC-derived cardiomyocytes (hESC-CMs) expressed several cardiomyocyte-specific markers including cTnT, MLC2a, and α-SA, but not pluripotency markers, such as OCT4 and NANOG. Patch clamp technique and RT-PCR revealed the expression of cardiomyocyte-specific Na⁺, Ca²⁺, and K⁺ channels and cardiac action potential in hESC-CMs. To explore the potential use of hESC-CMs as functional cardiomyocytes for drug discovery and cardiotoxicity screening, we examined the effects of bisindolylmaleimide (BIM) (I), which inhibits native cardiac Ca²⁺ channels, on the Ca²⁺ channel activity of hESC-CMs. We observed a similar response for the BIM (I)-induced modulation of Ca²⁺ channels between hESC-CMs and native cardiomyocytes through L-type Ca²⁺ channel current. These results suggest that hESC-CMs can be useful for evaluation of pharmaceutical efficacy and safety of novel drug candidate in cardiac research.

更新日期：2017-10-23

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