Department of Mechanical Engineering, University of California Santa Barbara, Santa Barbara, CA, 93109, USA.
Biomolecular Science and Engineering Program, University of California Santa Barbara, Santa Barbara, CA, 93109, USA.
Adv Healthc Mater. 2020 Apr;9(8):e1901656. doi: 10.1002/adhm.201901656. Epub 2020 Apr 9.
Cardiomyocytes are the motor units that drive the contraction and relaxation of the heart. Traditionally, testing of drugs for cardiotoxic effects has relied on primary cardiomyocytes from animal models and focused on short-term, electrophysiological, and arrhythmogenic effects. However, primary cardiomyocytes present challenges arising from their limited viability in culture, and tissue from animal models suffers from a mismatch in their physiology to that of human heart muscle. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can address these challenges. They also offer the potential to study not only electrophysiological effects but also changes in cardiomyocyte contractile and mechanical function in response to cardiotoxic drugs. With growing recognition of the long-term cardiotoxic effects of some drugs on subcellular structure and function, there is increasing interest in using hiPSC-CMs for in vitro cardiotoxicity studies. This review provides a brief overview of techniques that can be used to quantify changes in the active force that cardiomyocytes generate and variations in their inherent stiffness in response to cardiotoxic drugs. It concludes by discussing the application of these tools in understanding how cardiotoxic drugs directly impact the mechanobiology of cardiomyocytes and how cardiomyocytes sense and respond to mechanical load at the cellular level.
心肌细胞是驱动心脏收缩和舒张的动力单元。传统上，心脏毒性药物的测试依赖于动物模型的原代心肌细胞，并侧重于短期的电生理和致心律失常作用。然而，原代心肌细胞在培养中存在着活力有限的挑战，并且动物模型的组织在生理学上与人类心肌不匹配。人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）可以解决这些挑战。它们还提供了研究心肌细胞电生理作用以及对心脏毒性药物的收缩和机械功能变化的潜力。随着人们越来越认识到一些药物对亚细胞结构和功能的长期心脏毒性作用，人们越来越有兴趣使用 hiPSC-CMs 进行体外心脏毒性研究。这篇综述简要概述了可用于定量测量心肌细胞产生的主动力变化以及对心脏毒性药物固有硬度变化的技术。最后讨论了这些工具在理解心脏毒性药物如何直接影响心肌细胞的机械生物学以及心肌细胞如何在细胞水平上感知和响应机械负荷方面的应用。
