Human Hepatocytes with Drug Metabolic Function Induced from Fibroblasts by Lineage Reprogramming

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• 作者：Yuanyuan Du¹ ; ⁷ ; Jinlin Wang² ; ⁷ ; Jun Jia¹ ; ² ; ⁷ ; Nan Song¹ ; ² ; ⁷ ; Chengang Xiang¹ ; ⁷ ; Jun Xu¹ ; Zhiyuan Hou⁴ ; Xiaohua Su¹ ; Bei Liu² ; Tao Jiang⁵ ; Dongxin Zhao¹ ; Yingli Sun⁶ ; Jian Shu¹ ; Qingliang Guo⁵ ; Ming Yin¹ ; Da Sun² ; Shichun Lu⁵ ; ^{lsc620213@aliyun.com" class="auth_mail} ; Yan Shi² ; ^{shiyan@pkusz.edu.cn" class="auth_mail} ; Hongkui Deng¹ ; ² ; ³ ; ^{hongkui_deng@pku.edu.cn" class="auth_mail}
• 刊名：Cell Stem Cell
• 出版年：6 March, 2014
• 年：2014
• 卷：14
• 期：3
• 页码：394-403
• 全文大小：3372 K

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Summary

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^{鈭?鈭?/sup>/纬c鈭?鈭?/sup> mice and secrete more than 300聽渭g/ml human ALBUMIN in聽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.}