Human Hepatocytes with Drug Metabolic Function Induced from Fibroblasts by Lineage Reprogramming
Human Hepatocytes with Drug Metabolic Function Induced from Fibroblasts by Lineage Reprogramming
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DOI：
10.1016/j.stem.2014.01.008
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发表时间：
2014-03-06
期刊：
影响因子：
23.9
通讯作者：
Deng, Hongkui
中科院分区：
文献类型：
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作者：
Du, Yuanyuan;Wang, Jinlin;Deng, Hongkui
获得功能齐全的细胞类型是药物发现和再生医学的主要挑战。目前，这一关键问题仍缺乏根本解决办法。在这里，我们表明，功能性人诱导肝细胞（hiHeps）可以产生自成纤维细胞过表达的肝命运转换因子HNF 1A，HNF 4A，和HNF 6沿着与成熟因子ATF 5，PROX 1，CEBPA。hiHep表达一系列I相和II相药物代谢酶和III相药物转运蛋白。重要的是，hiHep和新鲜分离的原代人肝细胞之间的CYP 3A 4、CYP 1A 2、CYP 2B 6、CYP 2C 9和CYP 2C 19代谢活性相当。移植的hiHep在Tet-uPA/Rag 2（-/-）/γ c（-/-）小鼠的肝脏中重新填充高达30%，并在体内分泌超过300 μ g/ml的人白蛋白。我们的数据表明，具有药物代谢功能的人肝细胞可以通过谱系重编程产生，从而为药物应用提供细胞资源。
Obtaining fully functional cell types is a major challenge for drug discovery and regenerative medicine. Currently, a fundamental solution to this key problem is still lacking. Here, we show that functional human induced hepatocytes (hiHeps) can be generated from fibroblasts by overexpressing the hepatic fate conversion factors HNF1A, HNF4A, and HNF6 along with the maturation factors ATF5, PROX1, and CEBPA. hiHeps express a spectrum of phase I and II drug-metabolizing enzymes and phase III drug transporters. Importantly, the metabolic activities of CYP3A4, CYP1A2, CYP2B6, CYP2C9, and CYP2C19 are comparable between hiHeps and freshly isolated primary human hepatocytes. Transplanted hiHeps repopulate up to 30% of the livers of Tet-uPA/Rag2(-/-)/gamma c(-/-) mice and secrete more than 300 mu g/ml human ALBUMIN in vivo. Our data demonstrate that human hepatocytes with drug metabolic function can be generated by lineage reprogramming, thus providing a cell resource for pharmaceutical applications.