Enhancing the functional maturity of hiPSC-derived cardiomyocytes to assess inotropic compounds

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Xiaoyu Zhang , Praful Aggarwal , Ulrich Broeckel , Yama A. Abassi
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引用次数: 1

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) present an attractive in vitro platform to model safety and toxicity assessments—notably screening pro-arrhythmic compounds. The utility of the platform is stymied by a hiPSC-CM contractile apparatus and calcium handling mechanism akin to fetal phenotypes, evidenced by a negative force-frequency relationship. As such, hiPSC-CMs are limited in their ability to assess compounds that modulate contraction mediated by ionotropic compounds (Robertson, Tran, & George, 2013). To address this limitation, we utilize Agilent's xCELLigence Real-Time Cell Analyzer ePacer (RTCA ePacer) to enhance hiPSC-CM functional maturity. A continuous, progressive increase of electrical pacing is applied to hiPSC-CMs for up to 15 days. Contraction and viability are recorded by measurement of impedance using the RTCA ePacer. Our data confirms hiPSC-CMs inherently demonstrate a negative impedance amplitude frequency that is reversed after long-term electrical pacing. The data also indicate positive inotropic compounds increase the contractility of paced cardiomyocytes and calcium handling machinery is improved. Increased expression of genes critical to cardiomyocyte maturation further underscores the maturity of paced cells. In summary, our data suggest the application of continuous electrical pacing can functionally mature hiPSC-CMs, enhancing cellular response to positive inotropic compounds and improving calcium handling.

Summary

Long-term electrical stimulation of hiPSC-CM leads to functional maturation enabling predictive assessment of inotropic compounds.

增强hipsc来源的心肌细胞的功能成熟度以评估肌力化合物。
人诱导多能干细胞来源的心肌细胞(hiPSC-CMs)提供了一个有吸引力的体外平台来模拟安全性和毒性评估-特别是筛选促心律失常化合物。该平台的实用性受到hiPSC-CM收缩装置和类似于胎儿表型的钙处理机制的阻碍,证明了负力-频率关系。因此,hiPSC-CMs在评估由离子型化合物介导的调节收缩的化合物方面能力有限(Robertson, Tran, & George, 2013)。为了解决这一限制,我们利用安捷伦的xCELLigence实时细胞分析仪ePacer (RTCA ePacer)来提高hiPSC-CM功能的成熟度。对hiPSC-CMs持续渐进增加电起搏长达15天。收缩和活力是通过使用RTCA ePacer测量阻抗来记录的。我们的数据证实hiPSC-CMs固有地表现出负阻抗振幅频率,在长期电起搏后反转。数据还表明,正性肌力化合物增加了有节奏的心肌细胞的收缩力,钙处理机制得到改善。对心肌细胞成熟至关重要的基因表达的增加进一步强调了节律细胞的成熟。总之,我们的数据表明,持续电起搏可以在功能上使hiPSC-CMs成熟,增强细胞对正性肌力化合物的反应,改善钙处理。总结:长期电刺激hiPSC-CM可导致功能成熟,从而对肌力化合物进行预测性评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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