在ReproTracker试验中实施三线分化,以改善致性评估
José M Horcas-Nieto1, Sabine Hartvelt1, Luke Flatt1
1Toxys B.V., Oegstgeest, Netherlands.
Frontiers in toxicology
|October 13, 2025
概括
这项研究增强了ReproTracker,一种人类干细胞测定方法,通过添加神经分化来改善对原体的检测. 扩展分析准确地识别出发育性毒素,有助于早期查出生缺陷风险.
科学领域:
- 毒理学 毒理学 毒理学
- 发展生物学 发展生物学
- 干细胞生物学 干细胞生物学
背景情况:
- 产物化合物在怀孕期间存在风险,导致出生缺陷.
- 基于人体的体外测试对于识别原体至关重要,因为物种的变化和动物试验的伦理问题.
- ReproTracker是一种基于人体诱导多能干细胞 (hiPSCs) 的测定方法,先前评估了肝细胞和心肌细胞的特异化.
研究的目的:
- 为了提高ReproTracker测定在识别潜在的原体的可预测性.
- 为了评估扩展hiPSC差异化试验的性能,包括神经谱系承诺.
主要方法:
- 扩展了ReproTracker试验,将hiPSC分化纳入神经状细胞.
- 使用51种已知的体内原体和非原体,包括ICH S5参考化合物,评估了试验的性能.
- 结合形态分析和时间依赖的生物标志物表达分析.
主要成果:
- 优化的试验确定了以前的肝细胞/心肌细胞试验中遗漏的 (神经发育) 毒素.
- 检测到的化合物选择性地降低了神经皮质 (PAX6) 和神经红 (NESTIN) 标志物,以剂量依赖的方式.
- 测定精度从72.55%提高到86.27%,敏感度从67.50%提高到87.50%,具有神经分化.
结论:
- 三级分化 (肝细胞,心肌细胞,神经细胞) 显著扩大可检测到的致病原体的范围.
- 增强的ReproTracker试验是早期体外毒性查的宝贵工具.
- 这种改进的测试有助于识别潜在的人类病原体,减轻出生缺陷的风险.
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