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诱导多能干细胞肝细胞样细胞和原发性人类肝细胞的比较转录组和表型分析

Neeti Gandhi¹, Lauren Wills², Kyle Akers³

¹Department of Chemical Engineering, Virginia Tech, 333 Kelly Hall, Blacksburg, VA, 24061, USA.

Cell and tissue research

|February 18, 2024

概括

初级人类肝细胞 (PHHs) 与诱导性肝细胞样细胞 (iHLCs) 相比显示出不同的基因表达和功能. RNA测序揭示了胆汁分泌,TCA循环,尿素生产和药物代谢的显著差异,表明iHLCs不能完全复制PHH功能.

科学领域:

肝病学和干细胞生物学
基因组学和分子生物学

背景情况:

初级人类肝细胞 (PHHs) 对于肝脏研究至关重要,但其可用性有限.
诱导性肝细胞样细胞 (iHLCs) 提供了一个潜在的替代方案,但对它们的功能成熟度和表型特征提出了担忧.
了解PHHs和iHLCs之间的分子和功能差异对于准确的体外肝脏建模至关重要.

研究的目的:

为了全面比较PHHs和iHLCs的基因表达特征和关键肝功能.
为了确定特定的途径和基因,这些两种细胞类型之间有不同的调节.
在胆汁分泌,代谢过程和药物生物转化方面评估iHLCs的功能能力.

主要方法:

用RNA测序 (RNA-seq) 来分析PHH和iHLC中的基因表达模式.
对特定基因表达水平的定量分析,包括AQP9,UGT1A1和CYP450家族成员.
免疫染被用来可视化胆汁通道结构.
进行了功能性测试,以测量尿素的产生,并评估乙氨基和乙醇的药物代谢 (生物转化).

主要成果:

与iHLC相比,PHHs表现出参与胆汁分泌 (例如,AQP9,UGT1A1) 和TCA循环的基因表达显著更高.
在PHH中观察到胆管,但对于iHLCs没有明确详细说明.
与iHLC相比,PHHs显示出明显更高的尿素产量和P450细胞染色体 (CYP450) 活性,包括CYP2E1表达的大幅增加21,810倍.
药物代谢测定证实了PHH在基线和有毒剂治疗条件下都具有优越的生物转化能力.

结论:

在PHHs和iHLCs之间存在关键肝功能和基因表达特征的显著差异.
iHLCs不能完全复制PHHs的成熟功能表型,特别是在胆汁分泌,尿素合成和药物代谢中.
这些发现凸显了进一步研究的必要性,以完善iHLC分化协议,并验证它们在肝脏研究中作为PHH替代品的使用.

关键词:

基因表达基因表达肝细胞肝细胞肝细胞人类诱导的多能干细胞干细胞.在体外肝脏.在RNA-seqqq.

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