Kazemzadeh Dastjerd Mina, Merens Vincent, Smout Ayla, De Wolf Rebeca, Chesné Christophe, Verfaillie Catherine, Verhulst Stefaan, van Grunsven Leo A
Liver Cell Biology Research Group, Vrije Universiteit Brussel, 1090 Brussel, Belgium.
Biopredic International SARL, Parc de la Bretech, 35760 Saint Grégoire, France.
Cells. 2025 Jun 26;14(13):983. doi: 10.3390/cells14130983.
Liver fibrosis majorly impacts global health, necessitating the development of in vitro models to study disease mechanisms and develop drug therapies. Relevant models should at least include hepatocytes and hepatic stellate cells (HSCs) and ideally use three-dimensional cultures to mimic in vivo conditions. Induced pluripotent stem cells (iPSCs) allow for patient-specific liver modelling, but current models based on iPSC-derived hepatocytes (iHepatocytes) and HSCs (iHSCs) still lack key functions. We developed organoids of iHepatocytes and iHSCs and compared them to HepaRG and primary HSC organoids. RNA sequencing analysis comparison of these cultures identified a potential role for the transcription factor RXRA in hepatocyte differentiation and HSC quiescence. Treating cells with the RXRA ligand 9-cis-retinoic acid (9CRA) promoted iHepatocyte metabolism and iHSC quiescence. In organoids, 9CRA enhanced fibrotic response to TGF-β and acetaminophen, highlighting its potential for refining iPSC-based liver fibrosis models to more faithfully replicate human drug-induced liver injury and fibrotic conditions.
肝纤维化对全球健康有重大影响，因此需要开发体外模型来研究疾病机制并开发药物疗法。相关模型至少应包括肝细胞和肝星状细胞（HSC），理想情况下应使用三维培养来模拟体内条件。诱导多能干细胞（iPSC）可实现针对患者的肝脏建模，但目前基于iPSC衍生的肝细胞（iHepatocytes）和HSC（iHSCs）的模型仍缺乏关键功能。我们开发了iHepatocytes和iHSCs的类器官，并将它们与HepaRG和原代HSC类器官进行比较。对这些培养物的RNA测序分析比较确定了转录因子RXRA在肝细胞分化和HSC静止中的潜在作用。用RXRA配体9-顺式视黄酸（9CRA）处理细胞可促进iHepatocyte代谢和iHSC静止。在类器官中，9CRA增强了对TGF-β和对乙酰氨基酚的纤维化反应，突出了其在优化基于iPSC的肝纤维化模型以更忠实地复制人类药物性肝损伤和纤维化病症方面的潜力。
