利用肝脏类器官探究CEBPD和HMGA2对胆管细胞向肝细胞转分化的作用  

Study on the Roles of CEBPD and HMGA2 in Transdifferentiation from Cholangiocytes to Hepatocytes with Liver Ductal Organoids

作　　者：金丹 魏劲松 赵冰 JIN Dan;WEI Jingsong;ZHAO Bing(School of Life Sciences,Fudan University,Shanghai 200438,China)

机构地区：[1]复旦大学生命科学学院,上海200438

出　　处：《复旦学报（自然科学版）》2022年第2期158-166,共9页Journal of Fudan University：Natural Science

基　　金：国家重点研发计划(2018YFA0109400);国家自然科学基金优秀青年基金(32022022)。

摘　　要：肝脏是人体内最大的实质器官,负责机体的代谢解毒,具有较强的再生能力,在重度损伤条件下胆管细胞能够转分化为肝实质细胞,以补充损伤的肝实质细胞,但是具体机制尚不清楚。胆管类器官在体外可长期扩增并保持向肝实质细胞分化的潜能,同时利用腺相关病毒AAV载体可实现胆管类器官高效基因操纵。我们结合AAV介导的基因操纵与胆管类器官分化模型,探究了转录因子HMGA2及CEBPD在肝脏细胞谱系转化过程中的重要功能。研究结果发现过表达HMGA2能够抑制胆管细胞向肝实质细胞的分化,而过表达CEBPD可以促进胆管细胞向肝实质细胞分化。我们的工作揭示了HMGA2和CEBPD作为新的转录调节因子,可能参与胆管细胞的谱系维持以及肝实质细胞的分化。As the largest parenchymal organ in the human body, liver is mainly responsible for the metabolism and detoxification and has potent regenerative ability. Under severe liver injury, cholangiocytes can be transdifferentiated into hepatocytes to supplement the injured liver parenchymal cells, but the underlying mechanism remains largely unclear. Liver bile ductal organoids can be expanded for a long time in vitro and differentiated into hepatocytes under defined condition. Efficient gene manipulation on liver bile duct organoids can be achieved using adeno-associated virus(AAV) gene delivery system. In combination with AAV-mediated gene manipulation and liver bile duct organoid differentiation model, we interrogated the roles of transcription factors HMGA2 and CEBPD in liver cell lineage conversion. Our results showed that overexpression of HMGA2 inhibited the differentiation of cholangiocytes into hepatocytes, while the opposite effect was observed when CEBPD was overexpressed. Our work reveals that HMGA2 and CEBPD may be involved in the lineage maintenance of cholangiocytes and differentiation into hepatocytes.

关 键 词：肝脏类器官 转分化 腺相关病毒 CCAAT/增强子结合蛋白δ 高迁移率蛋白A2 

分 类 号：Q34[生物学—遗传学]