Non-human primate and rodent embryonic stem cells are differentially sensitive to embryotoxic compounds.
Non-human primate and rodent embryonic stem cells are differentially sensitive to embryotoxic compounds.
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DOI：
10.1016/j.toxrep.2014.11.016
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发表时间：
2015
影响因子：
--
通讯作者：
Zur Nieden NI
中科院分区：
文献类型：
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作者：
Walker L;Baumgartner L;Keller KC;Ast J;Trettner S;Zur Nieden NI
许多工业化学品及其相应的副产品需要使用可靠和有效的测定方法进行全面的毒性评估。在致畸性评估方面，基于鼠的胚胎干细胞试验（EST）提供了一种有前途的解决方案，以筛选多个组织终点。然而，在EST中使用小鼠模型只能产生对人类发育，解剖学和生理学的有限理解。非人灵长类动物或人体外模型已被认为是鼠体外模型的一种理想和病理生理学替代方法。在这里，我们比较评估了非人灵长类动物胚胎干细胞（ESC）对骨骼致畸剂的敏感性与小鼠ESC，假设在体外试验中纳入非人灵长类动物细胞将增加人类安全性预测的可靠性。首先，比较了小鼠和新大陆猴（普通绒猴）的胚胎干细胞的成骨能力。然后，用先前报道的诱导骨致畸性的化合物处理细胞。钙化和MTT试验分别评价了对骨生成和细胞活力的影响。我们的数据表明，在这种胚胎毒性筛选中，绒猴胚胎干细胞的反应与小鼠胚胎干细胞不同，对化学品或化合物类别没有明显的依赖性，因此表明胚胎毒性筛选结果可能受到物种驱动的反应变化的影响。此外，观察到来源于恒河猴（一种旧大陆猴，并且在遗传学上比绒猴更接近人类）的ESC与绒猴ESC相比对测试化合物的反应不同。总之，这些结果表明，非人灵长类动物和小鼠ESC对胚胎毒性剂的反应存在显着差异。
Many industrial chemicals and their respective by-products need to be comprehensively evaluated for toxicity using reliable and efficient assays. In terms of teratogenicity evaluations, the murine-based embryonic stem cell test (EST) offers a promising solution to screen for multiple tissue endpoints. However, use of a mouse model in the EST can yield only a limited understanding of human development, anatomy, and physiology. Non-human primate or human in vitro models have been suggested to be a pharmacologically and pathophysiologically desirable alternative to murine in vitro models. Here, we comparatively evaluated the sensitivity of embryonic stem cells (ESCs) of a non-human primate to skeletal teratogens with mouse ESCs hypothesizing that inclusion of non-human primate cells in in vitro tests would increase the reliability of safety predictions for humans. First, osteogenic capacity was compared between ESCs from the mouse and a New World monkey, the common marmoset. Then, cells were treated with compounds that have been previously reported to induce bone teratogenicity. Calcification and MTT assays evaluated effects on osteogenesis and cell viability, respectively. Our data indicated that marmoset ESCs responded differently than mouse ESCs in such embryotoxicity screens with no obvious dependency on chemical or compound classes and thus suggest that embryotoxicity screening results could be affected by species-driven response variation. In addition, ESCs derived from rhesus monkey, an Old World monkey, and phylogenetically closer to humans than the marmoset, were observed to respond differently to test compounds than marmoset ESCs. Together these results indicate that there are significant differences in the responses of non-human primate and mouse ESC to embryotoxic agents.