Suter-Dick Laura, Alves Paula M, Blaauboer Bas J, Bremm Klaus-Dieter, Brito Catarina, Coecke Sandra, Flick Burkhard, Fowler Paul, Hescheler Jürgen, Ingelman-Sundberg Magnus, Jennings Paul, Kelm Jens M, Manou Irene, Mistry Pratibha, Moretto Angelo, Roth Adrian, Stedman Donald, van de Water Bob, Beilmann Mario
1University of Applied Sciences Northwestern Switzerland, School of Life Sciences, Muttenz, Switzerland.
2iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
Stem Cells Dev. 2015 Jun 1;24(11):1284-96. doi: 10.1089/scd.2014.0540. Epub 2015 Mar 31.
Industrial sectors perform toxicological assessments of their potential products to ensure human safety and to fulfill regulatory requirements. These assessments often involve animal testing, but ethical, cost, and time concerns, together with a ban on it in specific sectors, make appropriate in vitro systems indispensable in toxicology. In this study, we summarize the outcome of an EPAA (European Partnership of Alternatives to Animal Testing)-organized workshop on the use of stem cell-derived (SCD) systems in toxicology, with a focus on industrial applications. SCD systems, in particular, induced pluripotent stem cell-derived, provide physiological cell culture systems of easy access and amenable to a variety of assays. They also present the opportunity to apply the vast repository of existing nonclinical data for the understanding of in vitro to in vivo translation. SCD systems from several toxicologically relevant tissues exist; they generally recapitulate many aspects of physiology and respond to toxicological and pharmacological interventions. However, focused research is necessary to accelerate implementation of SCD systems in an industrial setting and subsequent use of such systems by regulatory authorities. Research is required into the phenotypic characterization of the systems, since methods and protocols for generating terminally differentiated SCD cells are still lacking. Organotypical 3D culture systems in bioreactors and microscale tissue engineering technologies should be fostered, as they promote and maintain differentiation and support coculture systems. They need further development and validation for their successful implementation in toxicity testing in industry. Analytical measures also need to be implemented to enable compound exposure and metabolism measurements for in vitro to in vivo extrapolation. The future of SCD toxicological tests will combine advanced cell culture technologies and biokinetic measurements to support regulatory and research applications. However, scientific and technical hurdles must be overcome before SCD in vitro methods undergo appropriate validation and become accepted in the regulatory arena.
工业部门对其潜在产品进行毒理学评估，以确保人类安全并满足监管要求。这些评估通常涉及动物试验，但出于伦理、成本和时间方面的考虑，再加上特定部门对动物试验的禁令，使得合适的体外系统在毒理学中不可或缺。在本研究中，我们总结了由欧洲替代动物试验伙伴关系（EPAA）组织的关于在毒理学中使用干细胞衍生（SCD）系统的研讨会成果，重点是工业应用。特别是诱导多能干细胞衍生的SCD系统，提供了易于获取且适用于各种检测的生理细胞培养系统。它们还提供了应用大量现有非临床数据来理解体外到体内转化的机会。存在来自多个毒理学相关组织的SCD系统；它们通常概括了生理学的许多方面，并对毒理学和药理学干预做出反应。然而，需要有针对性的研究来加速SCD系统在工业环境中的实施以及监管机构随后对这类系统的使用。由于仍然缺乏生成终末分化SCD细胞的方法和方案，因此需要对这些系统的表型特征进行研究。应促进生物反应器中的器官型3D培养系统和微尺度组织工程技术，因为它们能促进和维持分化并支持共培养系统。它们需要进一步开发和验证，以便在工业毒性测试中成功实施。还需要实施分析措施，以实现化合物暴露和代谢测量，用于体外到体内的外推。SCD毒理学测试的未来将结合先进细胞培养技术和生物动力学测量，以支持监管和研究应用。然而，在SCD体外方法经过适当验证并在监管领域被接受之前，必须克服科学和技术障碍。
