在人类多能干细胞衍生的肝脏二维细胞和三维器官模型中对CYP450基因调节的比较研究
Eunhye Kang1, Ji-Woo Kim1, Seongyea Jo1
1Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon, Republic of Korea.
Toxicology
|June 4, 2025
概括
人类多能干细胞衍生的肝脏器官因成熟的表观遗传调节而显示出比2D模型更高的药物代谢酶活性. 这表明表观遗传标记表明肝脏模型成熟,用于药物安全性和有效性测试.
科学领域:
- 干细胞生物学 干细胞生物学
- 肝病学 肝病学是一种肝病学.
- 药理学 药理学是指药理学的学科.
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 人类多能干细胞衍生肝脏模型 (2D HLC 和 HO) 对于药物评估至关重要.
- 2D HLCs表现出有限的药物代谢酶活性,特别是细胞染色体P450 (CYP450).
- 肝脏器官 (HOs) 显示出更成熟的特性,包括增强的CYP450表达,但调节机制尚不清楚.
研究的目的:
- 研究在肝脏器官 (HOs) 中增强CYP450表达背后的转录调节机制.
- 为了比较HOs中的表观遗传状态与初级人类肝细胞.
- 为了确定表观遗传调节是否影响hPSC衍生肝脏模型中的药物代谢和毒性.
主要方法:
- 在hPSC衍生肝脏模型的转录调节区域中识别表观遗传状态 (DNA甲基化,基因素乙化).
- 对比2D HLC,HO和原发性人肝细胞之间的表观遗传状态和CYP450基因表达.
- 评估核受体介导的诱导药物代谢基因 (CYP3A4,UGT1A1,MDR1) 在HO与2D HLCs.
主要成果:
- 与2D HLC相比,HO中的CYP450基因表达显著更高,与DNA甲基化降低和基因组H3 lysine27乙化增加相关.
- 患者表现出核受体基因 (CAR,PXR) 的更高表达.
- 与2D HLC相比,HOs通过核受体表现出更大的CYP3A4,UGT1A1和MDR1诱导.
结论:
- 成熟的表观遗传调节,特别是低甲基化和特定的基因素乙化模式,与肝脏有机体中增强的CYP450表达有关.
- 由于成熟的表观遗传调节和核受体活性,肝脏器官具有优越的药物代谢能力.
- 表观遗传成熟可以作为评估药物开发中hPSC衍生肝脏模型质量和可靠性的可靠指标.
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