Institute for Health and Consumer Protection, DG Joint Research Centre (JRC), European Commission, Systems Toxicology Unit , Via E. Fermi 2749, TP 580, 21027 Ispra (VA) , Italy +39 0332 785914 ; +39 0332 785336 ;
Expert Opin Drug Metab Toxicol. 2014 Jan;10(1):39-50. doi: 10.1517/17425255.2013.844228. Epub 2013 Oct 8.
Human stem cell lines and their derivatives, as alternatives to the use of animal cells or cancer cell lines, have been widely discussed as cellular models in predictive toxicology. However, the role of stem cells in the development of long-term toxicities and carcinogenesis has not received great attention so far, despite growing evidence indicating the relationship of stem cell damage to adverse effects later in life. However, testing this in vitro is a scientific/technical challenge in particular due to the complex interplay of factors existing under physiological conditions. Current major research programs in stem cell toxicity are not aiming to demonstrate that stem cells can be targeted by toxicants. Therefore, this knowledge gap needs to be addressed in additional research activities developing technical solutions and defining appropriate experimental designs.
The current review describes selected examples of the role of stem cells in the development of long-term toxicities in the brain, heart or liver and in the development of cancer.
The presented examples illustrate the need to analyze the contribution of stem cells to chronic toxicity in order to make a final conclusion whether stem cell toxicities are an underestimated risk in mechanism-based safety assessments. This requires the development of predictive in vitro models allowing the assessment of adverse effects to stem cells on chronic toxicity and carcinogenicity.
人类干细胞系及其衍生物作为替代动物细胞或癌细胞系的方法，已被广泛讨论作为预测毒理学中的细胞模型。然而，到目前为止，干细胞在长期毒性和致癌作用发展中的作用并没有得到很大的关注，尽管越来越多的证据表明干细胞损伤与生命后期的不良影响有关。然而，由于生理条件下存在的各种因素的复杂相互作用，在体外进行这项测试是一个科学/技术挑战。目前干细胞毒性的主要研究计划并不是旨在证明有毒物质可以靶向干细胞。因此，需要在开发技术解决方案和定义适当实验设计的额外研究活动中解决这一知识空白。
目前的综述描述了干细胞在大脑、心脏或肝脏的长期毒性发展以及癌症发展中作用的一些例子。
所呈现的例子说明了需要分析干细胞对慢性毒性的贡献，以便最终得出结论，即干细胞毒性是否是基于机制的安全性评估中被低估的风险。这需要开发预测性的体外模型，以评估对慢性毒性和致癌性的干细胞的不良影响。
