摘要
心脏毒性是药物研发失败的主要原因之一,也是临床前安全评价研究的难题之一。人胚胎干细胞和诱导型人多能干细胞均具有无限增殖、自我更新和多向分化的特性,为体外心脏毒性筛选实验提供了细胞资源。人胚胎干细胞和诱导型人多能干细胞诱导分化的心肌细胞相似,具有相同的形态结构,且随着培养时间的推移,功能性K+、Na+、Ca2+通道密度逐渐增加、心肌特异性基因ANF、α-MHC、MLC-2a的表达量增加,具有相似的动作电位时程和收缩性等特点,相当于幼稚型心肌细胞。将它们应用于已知作用药物的心脏毒性筛选,检测心肌细胞离子通道、动作电位、心脏损伤标志物、收缩功能的变化,获得与临床相似的结果。因此,建立人胚胎干细胞和诱导型人多能干细胞诱导分化心肌细胞的体外评价模型,大大减少了药物研发的时间和成本,克服了种属间的差异,推动了心脏毒性体外评价方法的发展。
Cardiovascular toxicity is one of the main reasons of the failure of the drug development, which is also a difficult problem in preclinical safety evaluation experiment. The unlimited proliferation, self-renewal, multi-directional differentiation properties of human embryonic stem cells （hESCs） and human induced pluripotent stem cells （hiPSCs） provide cell resources in vitro cardiac toxicity screening experiment, hESC and hiPSCs derived cardiomyocytes have been reported to share a high degree of similarity in morphology structure, and over time the density of functional potassium, sodium, calcium channels gradually increase, the key cardiac structural and functional genes ANF, a-MHC, MLC-2a robustly upregulate, electtophysiological and biochemical characteristics are similar. These characteristics are similar to that of immature cardiomyocytes. The applications of hESCs and hiPSCs in drug screening, including ion channels, action potentials, biomarkers of cardiotoxicity and contraction,and these demonstrated pharmacologic responses similar to those in clinical observations. Establishment of the model in vitro reduces the time and the cost, overcomes the problem of species specificity and promotes the development of cardiotoxicity.
出处
《中国细胞生物学学报》
CAS
CSCD
北大核心
2014年第1期143-148,共6页
Chinese Journal of Cell Biology
基金
"十二五"国家科技重大专项新药创制重大专项(批准号:2012ZX09302002)资助的课题~~
关键词
人多能干细胞
心肌细胞
心脏毒性
安全性评价
human pluripotent stem cells
cardiomyocytes
cardiotoxicity
safety assessment
