Khan Jaffar M, Lyon Alexander R, Harding Sian E
Royal Brompton and Harefield NHS Trust, London, UK National Heart and Lung Institute, Imperial College, London, UK.
Br J Pharmacol. 2013 May;169(2):304-17. doi: 10.1111/j.1476-5381.2012.02118.x.
The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell-derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient-specific cardiomyocytes, allowing both generic and disease- and patient-specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of 'adult-like' cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell-derived cardiomyocytes and explore what the future may hold for their use in pharmacology.
当前的药物筛选模型存在缺陷，尤其是在检测心脏副作用方面。人类干细胞衍生的心肌细胞有助于早期心脏毒性检测和新药研发。过去十年的研究已培育出人类胚胎干细胞，可作为潜在的精确人类心肌细胞来源，但伦理限制以及建立细胞系的低效性限制了它们的应用。诱导多能干细胞无需使用人类胚胎，还有产生患者特异性心肌细胞的额外优势，可进行通用的、针对疾病和患者的药理学筛选，以及通过疾病建模进行药物研发。一个关键问题是，从人类成纤维细胞组织可靠且可重复地生成“类成人”心肌细胞，是否已达到足够标准，从而从验证阶段推进到实际安全使用和药物研发阶段。本综述将强调建立新实验系统的必要性，评估人类诱导多能干细胞衍生心肌细胞的有效性，并探讨其在药理学应用中的未来前景。
