Direct Reprogramming of Human Fibroblasts to Functional and Expandable Hepatocytes
Direct Reprogramming of Human Fibroblasts to Functional and Expandable Hepatocytes
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将人成纤维细胞直接重编程为功能性和可扩展的肝细胞
DOI：
10.1016/j.stem.2014.01.003
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发表时间：
2014-03-06
期刊：
影响因子：
23.9
通讯作者：
Hui, Lijian
中科院分区：
文献类型：
--
作者：
Huang, Pengyu;Zhang, Ludi;Hui, Lijian
产生大量功能性人类肝细胞用于基于细胞的肝病治疗方法是一个重要且尚未实现的目标。将成纤维细胞直接重编程为肝谱系可以为这个问题提供解决方案，但迄今为止仅在小鼠细胞中实现。在这里，我们通过 FOXA3、HNF1A 和 HNF4A 的慢病毒表达，从成纤维细胞中产生了人诱导肝细胞 (hiHeps)。 hiHeps表达肝脏基因程序，可以在体外扩增，并显示成熟肝细胞的功能特征，包括细胞色素P450酶活性和胆道药物清除。 hiHeps 移植到由于延胡索酰乙酰乙酸脱氢酶 (Fah) 缺乏而导致伴刀豆球蛋白 A 诱导的急性肝功能衰竭和致命性代谢性肝病的小鼠体内后，hiHeps 可以恢复肝功能并延长生存期。总的来说，我们的结果证明非肝人类细胞成功谱系转化为成熟肝细胞，具有生物医学和制药应用的潜力。
The generation of large numbers of functional human hepatocytes for cell-based approaches to liver disease is an important and unmet goal. Direct reprogramming of fibroblasts to hepatic lineages could offer a solution to this problem but so far has only been achieved with mouse cells. Here, we generated human induced hepatocytes (hiHeps) from fibroblasts by lentiviral expression of FOXA3, HNF1A, and HNF4A. hiHeps express hepatic gene programs, can be expanded in vitro, and display functions characteristic of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance. Upon transplantation into mice with concanavalin-A-induced acute liver failure and fatal metabolic liver disease due to fumarylacetoacetate dehydrolase (Fah) deficiency, hiHeps restore the liver function and prolong survival. Collectively, our results demonstrate successful lineage conversion of nonhepatic human cells into mature hepatocytes with potential for biomedical and pharmaceutical applications.