环素A对从诱导的多能干细胞中分化的内皮细胞的毒性:组装一个不利的结局途径
Zahra Mazidi1, Matthias Wieser2, Nicoleta Spinu3
1Evercyte GmbH, Leberstrasse 20, 1110 Vienna, Austria; Institute of Molecular Biotechnology, Department of Biotechnology, BOKU University, Muthgasse 18, 1190 Vienna, Austria.
概括
环素A (CSA) 通过诱导内皮细胞毒性导致血管功能障碍. 这项研究揭示了CSA通过活性氧物种 (ROS) 和线粒体功能障碍损害血管生成,建立了潜在的不良结果途径 (AOP).
科学领域:
- 毒理学 毒理学 毒理学
- 干细胞生物学 干细胞生物学
- 血管生物学 血管生物学
背景情况:
- 环素A (CSA) 是一种具有已知的血管副作用的免疫抑制剂.
- CSA诱导的内皮细胞毒性的确切机制及其与不良结果途径 (AOPs) 的联系仍然不清楚.
研究的目的:
- 使用体外模型研究CSA对血管生成的机械毒理学.
- 为了确定CSA介导的内皮细胞毒性潜在的AOP.
主要方法:
- 差异化诱导多能干细胞 (iPSCs) 转化为内皮细胞 (ECs),用于体外研究.
- 在iPSC衍生的EC上使用CSA进行了剂量和时间的细胞毒性实验.
- 分析了转录组数据,并通过体外测试证实了这些发现,包括ROS和线粒体功能测试.
主要成果:
- 在iPSC衍生的EC中,CSA诱导了活性氧物种 (ROS) 和线粒体功能障碍.
- CSA显著损害了血管新生,这是一个由ROS诱导介导的过程.
- 实验数据与文献进行了整合,以提出CSA毒性的AOP.
结论:
- 对内皮细胞的CSA毒性涉及ROS诱导和线粒体功能障碍,导致血管生成受损.
- 拟议的AOP为了解CSA的血管影响和开发预测毒理模型提供了一个框架.
- 从iPSC衍生的EC作为一种有价值的体外模型,用于研究药物毒性和减少动物实验.
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