Stella Stoter Aaltje Maria, Hirt Marc N, Stenzig Justus, Weinberger Florian
Institute of Experimental Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany; German Centre for Cardiovascular Research, Hamburg, Kiel, and Lübeck, Germany.
Institute of Experimental Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Germany; German Centre for Cardiovascular Research, Hamburg, Kiel, and Lübeck, Germany.
Clin Ther. 2020 Oct;42(10):1892-1910. doi: 10.1016/j.clinthera.2020.08.012. Epub 2020 Sep 13.
Adverse cardiovascular drug effects pose a substantial medical risk and represent a common cause of drug withdrawal from the market. Thus, current in vitro assays and in vivo animal models still have shortcomings in assessing cardiotoxicity. A human model for more accurate preclinical cardiotoxicity assessment is highly desirable. Current differentiation protocols allow for the generation of human pluripotent stem cell-derived cardiomyocytes in basically unlimited numbers and offer the opportunity to study drug effects on human cardiomyocytes. The purpose of this review is to provide a brief overview of the current approaches to translate studies with pluripotent stem cell-derived cardiomyocytes from basic science to preclinical risk assessment.
A review of the literature was performed to gather data on the pathophysiology of cardiotoxicity, the current cardiotoxicity screening assays, stem cell-derived cardiomyocytes, and their application in cardiotoxicity screening.
There is increasing evidence that stem cell-derived cardiomyocytes predict arrhythmogenicity with high accuracy. Cardiomyocyte immaturity represents the major limitation so far. However, strategies are being developed to overcome this hurdle, such as tissue engineering. In addition, stem cell-based strategies offer the possibility to assess structural drug toxicity (eg, by anticancer drugs) on complex models that more closely mirror the structure of the heart and contain endothelial cells and fibroblasts.
Pluripotent stem cell-derived cardiomyocytes have the potential to substantially change how preclinical cardiotoxicity screening is performed. To which extent they will replace or complement current approaches is being evaluated.
心血管药物不良反应构成重大医疗风险，是药物退市的常见原因。因此，目前的体外试验和体内动物模型在评估心脏毒性方面仍存在缺陷。非常需要一种能进行更准确临床前心脏毒性评估的人体模型。目前的分化方案能够生成数量基本不受限的人多能干细胞衍生心肌细胞，为研究药物对人心肌细胞的作用提供了机会。本综述的目的是简要概述当前将多能干细胞衍生心肌细胞研究从基础科学转化为临床前风险评估的方法。
进行文献综述，以收集有关心脏毒性病理生理学、当前心脏毒性筛查试验、干细胞衍生心肌细胞及其在心脏毒性筛查中的应用的数据。
越来越多的证据表明，干细胞衍生心肌细胞能够高精度地预测致心律失常性。心肌细胞不成熟是目前的主要限制因素。然而，正在开发克服这一障碍的策略，如组织工程。此外，基于干细胞的策略提供了在更接近心脏结构且包含内皮细胞和成纤维细胞的复杂模型上评估结构性药物毒性（如抗癌药物所致）的可能性。
多能干细胞衍生心肌细胞有可能极大地改变临床前心脏毒性筛查的方式。它们将在多大程度上取代或补充现有方法仍有待评估。
