Department of Neurology, Vanderbilt Kennedy Center, Vanderbilt University, Nashville, TN, United States.
Neurotoxicology. 2012 Jun;33(3):518-29. doi: 10.1016/j.neuro.2012.02.005. Epub 2012 Feb 11.
An important goal of neurotoxicological research is to provide relevant and accurate risk assessment of environmental and pharmacological agents for populations and individuals. Owing to the challenges of human subject research and the real possibility of species specific toxicological responses, neuronal lineages derived from human embryonic stem cells (hESCs) and human neuronal precursors have been offered as a potential solution for validation of neurotoxicological data from model organism systems in humans. More recently, with the advent of induced pluripotent stem cell (iPSC) technology, there is now the possibility of personalized toxicological risk assessment, the ability to predict individual susceptibility to specific environmental agents, by this approach. This critical advance is widely expected to facilitate analysis of cellular physiological pathways in the context of human neurons and the underlying genetic factors that lead to disease. Thus this technology opens the opportunity, for the first time, to characterize the physiological, toxicological, pharmacological and molecular properties of living human neurons with identical genetic determinants as human patients. Furthermore, armed with a complete clinical history of the patients, human iPSC (hiPSC) studies can theoretically compare patients and at risk groups with distinct sensitivities to particular environmental agents, divergent clinical outcomes, differing co-morbidities, and so forth. Thus iPSCs and neuronal lineages derived from them may reflect the unique genetic blueprint of the individuals from which they are generated. Indeed, iPSC technology has the potential to revolutionize scientific approaches to human health. However, before this overarching goal can be reached a number of technical and theoretical challenges must be overcome. This review seeks to provide a realistic assessment of hiPSC technology and its application to risk assessment and mechanistic studies in the area of neurotoxicology. We seek to identify, prioritize, and detail the primary hurdles that need to be overcome if personalized toxicological risk assessment using patient-derived iPSCs is to succeed.
神经毒理学研究的一个重要目标是为人群和个体提供环境和药理学制剂相关且准确的风险评估。由于人体研究存在挑战，以及物种特异性毒理学反应的真实可能性，因此已经提出源自人胚胎干细胞（hESC）和人神经前体细胞的神经元谱系作为验证来自人类模式生物系统的神经毒理学数据的潜在解决方案。最近，随着诱导多能干细胞（iPSC）技术的出现，现在有可能通过这种方法对特定环境制剂的个体毒性易感性进行个性化毒性风险评估，即能够预测个体对特定环境制剂的敏感性。这项关键进展有望广泛促进在人类神经元背景下分析细胞生理途径，以及导致疾病的潜在遗传因素。因此，这项技术首次为我们提供了机会，使我们能够对具有与人类患者相同遗传决定因素的活的人类神经元的生理、毒性、药理和分子特性进行特征描述。此外，借助患者的完整临床病史，理论上人类 iPSC（hiPSC）研究可以将具有不同敏感性的患者和高危人群与特定环境制剂进行比较，还可以对不同的临床结果、不同的合并症等进行比较。因此，hiPSC 和源自它们的神经元谱系可能反映出它们所源自的个体的独特遗传蓝图。事实上，iPSC 技术有可能彻底改变人类健康的科学研究方法。然而，在实现这一总体目标之前，必须克服许多技术和理论上的挑战。本综述旨在对 hiPSC 技术及其在神经毒理学领域的风险评估和机制研究中的应用进行现实评估。我们试图确定、确定优先级并详细说明，如果要使用源自患者的 iPSC 进行个性化毒性风险评估，则需要克服的主要障碍。
