Qu Yusheng, Feric Nicole, Pallotta Isabella, Singh Rishabh, Sobbi Rooz, Vargas Hugo M
Amgen Research, Translational Safety & Bioanalytical Sciences, Thousand Oaks, CA, USA.
TARA Biosystems, New York, NY, USA.
J Pharmacol Toxicol Methods. 2020 Sep;105:106886. doi: 10.1016/j.vascn.2020.106886. Epub 2020 Jul 3.
To develop therapeutics for cardiovascular disease, especially heart failure, translational models for assessing cardiac contractility are necessary for preclinical target validation and lead optimization. The availability of stem cell-derived cardiomyocytes (SC-CM) has generated a great opportunity in developing new in-vitro models for assessing cardiac contractility. However, the immature phenotype of SC-CM is a well-recognized limitation in inotropic evaluation, especially regarding the lack of or diminished positive inotropic response to β-adrenergic agonists. Recent development of 3D engineered cardiac tissues (ECTs) using human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CM) in the Biowire II platform has shown improved maturation. To evaluate their suitability to detect drug-induced changes in cardiac contractility, positive inotropes with diverse mechanisms, including β-adrenergic agonists, PDE3 inhibitors, Ca-sensitizers, myosin and troponin activators, and an apelin receptor agonist, were tested blindly. A total of 8 compounds were evaluated, including dobutamine, milrinone, pimobendan, levosimendan, omecamtiv mecarbil, AMG1, AMG2, and pyr-apelin-13. Contractility was evaluated by analyzing the amplitude, velocity and duration of contraction and relaxation. All tested agents, except pyr-apelin-13, increased contractility by increasing the amplitude of contraction and velocity. In addition, myosin and troponin activators increase contraction duration. These results indicate that ECTs generated in the Biowire II platform can identify inotropes with different mechanisms and provides a human-based in-vitro model for evaluating potential therapeutics.
为开发心血管疾病尤其是心力衰竭的治疗方法，用于评估心脏收缩力的转化模型对于临床前靶点验证和先导化合物优化至关重要。干细胞衍生的心肌细胞（SC-CM）的可用性为开发评估心脏收缩力的新型体外模型创造了巨大机会。然而，SC-CM的未成熟表型是变力性评估中一个公认的局限性，特别是在对β-肾上腺素能激动剂缺乏或减弱的正性肌力反应方面。最近在Biowire II平台上使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）开发的3D工程心脏组织（ECT）显示出成熟度有所提高。为了评估它们检测药物诱导的心脏收缩力变化的适用性，对包括β-肾上腺素能激动剂、磷酸二酯酶3抑制剂、钙敏化剂、肌球蛋白和肌钙蛋白激活剂以及阿片肽受体激动剂在内的多种机制的正性肌力药物进行了盲法测试。总共评估了8种化合物，包括多巴酚丁胺、米力农、匹莫苯丹、左西孟旦、奥米卡替麦卡比、AMG1、AMG2和吡阿片肽-13。通过分析收缩和舒张的幅度、速度和持续时间来评估收缩力。除吡阿片肽-13外，所有测试药物均通过增加收缩幅度和速度来增加收缩力。此外，肌球蛋白和肌钙蛋白激活剂可增加收缩持续时间。这些结果表明，在Biowire II平台上生成的ECT可以识别具有不同机制的正性肌力药物，并为评估潜在治疗药物提供基于人体的体外模型。
