Davila Julio C, Cezar Gabriela G, Thiede Mark, Strom Stephen, Miki Toshio, Trosko James
Pfizer, Inc., Pfizer Global Research and Development, St. Louis, Missouri 63167, USA.
Toxicol Sci. 2004 Jun;79(2):214-23. doi: 10.1093/toxsci/kfh100. Epub 2004 Mar 10.
In recent years, stem cells have been the subject of increasing scientific interest because of their utility in numerous biomedical applications. Stem cells are capable of renewing themselves; that is, they can be continuously cultured in an undifferentiated state, giving rise to more specialized cells of the human body such as heart, liver, bone marrow, blood vessel, pancreatic islet, and nerve cells. Therefore, stem cells are an important new tool for developing unique, in vitro model systems to test drugs and chemicals and a potential to predict or anticipate toxicity in humans. The following review provides an overview of the applications of stem cell technology in the area of toxicology. Specifically, this review addresses core technologies that are emerging in the field and how they could fulfill critical safety issues such as QT prolongation and hepatotoxicity, two leading causes of failures in preclinical development of new therapeutic drugs. We report how adult stem cells derived from various sources, such as human bone marrow and placenta, can potentially generate suitable models for cardiotoxicity, hepatotoxicity, genotoxicity/epigenetic and reproductive toxicology screens. Additionally, this review addresses the role and advantages of embryonic stem cells in the aforementioned models for toxicity and how genetic selection is employed to overcome major limitations to the implementation of stem cell-based in vitro models for toxicology.
近年来，干细胞因其在众多生物医学应用中的效用而受到越来越多的科学关注。干细胞能够自我更新；也就是说，它们可以在未分化状态下持续培养，产生人体中更特化的细胞，如心脏、肝脏、骨髓、血管、胰岛和神经细胞。因此，干细胞是开发独特的体外模型系统以测试药物和化学品以及预测或预估人类毒性的重要新工具。以下综述概述了干细胞技术在毒理学领域的应用。具体而言，本综述探讨了该领域正在兴起的核心技术，以及它们如何解决关键的安全问题，如QT间期延长和肝毒性，这是新治疗药物临床前开发失败的两个主要原因。我们报告了源自各种来源（如人类骨髓和胎盘）的成体干细胞如何有可能为心脏毒性、肝毒性、遗传毒性/表观遗传学和生殖毒理学筛选生成合适的模型。此外，本综述还探讨了胚胎干细胞在上述毒性模型中的作用和优势，以及如何利用基因选择来克服基于干细胞的体外毒理学模型实施中的主要限制。
