[人类肝脏器官的应用在制药研究中]
Yukiko Ueyama-Toba1,2,3, Yanran Tong1,2, Hiroyuki Mizuguchi1,2,3
1Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University.
概括
人类肝脏有机体现在可以使用一种新的2D培养方法将其分化为高功能肝细胞. 这些有机原型肝细胞 (Org-HEPs) 显示药物代谢增强,适合临床前药物测试.
科学领域:
- 肝病学和再生医学 肝病学和再生医学
- 药物代谢和药理动力学
- 在体外毒理学中
背景情况:
- 人类肝脏有机体对药物代谢研究有希望,但表现出有限的肝功能.
- 提高初级人类肝细胞 (PHH) 衍生器官的功能能力对于临床前应用至关重要.
- 现有的有机体模型需要改进肝脏分化,以便准确的药物处置和毒性评估.
研究的目的:
- 开发和验证一种新的2D培养肝脏分化方法,用于PHH衍生器官.
- 显著增强器官衍生肝细胞 (Org-HEPs) 的肝功能和药物代谢酶活动.
- 评估Org-HEPs对临床前药物代谢,处置和肝毒性测试的有用性.
主要方法:
- 从冷保存的PHHs中建立了PHH衍生器官.
- 来自有机体的单细胞在2D培养,在原蛋白I型涂层板上培养.
- 使用各种化合物,细胞因子和生长因子选了最佳的肝分化条件.
主要成果:
- 2D培养方法成功地将PHH衍生器官分化为Org-HEPs,肝脏基因表达显著增加.
- 与母体有机体相比,RNA-seq分析揭示了Org-HEPs中高调的药理学相关基因表达.
- 对于关键的CYP酶 (CYP1A2,CYP2C8,CYP2E1,CYP3A4),Org-HEPs的代谢活动与PHHs相当.
- 在暴露于已知的肝毒药物时,Org-HEPs表现出与PHHs相似的细胞活力.
结论:
- 使用2D培养系统,可以有效地将PHH衍生器官分化为高功能肝细胞.
- 组织HEP代表了临床前药物代谢和处置研究的有价值的体外模型.
- 开发的Org-HEPs适用于准确的肝毒性测试,支持制药研究和药物开发.
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