title: Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming.
abstract: 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(-/-)/γc(-/-) mice and secrete more than 300 μg/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.
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Du
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Wang
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jia
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Song
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Chengang
authors.initials: C
authors.lastname: Xiang
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Beijing Vitalstar Biotechnology, Beijing 100012, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Hou
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Su
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Dongxin
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shu
authors.affiliation: Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Qingliang
authors.initials: Q
authors.lastname: Guo
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yin
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Da
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: lsc620213@aliyun.com.
authors.forename: Shichun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: shiyan@pkusz.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Peking University Stem Cell Research Center, Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: hongkui_deng@pku.edu.cn.
authors.forename: Hongkui
authors.initials: H
authors.lastname: Deng
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002469:Cell Separation; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D051379:Mice; D008807:Mice, Inbred BALB C; D013752:Tetracycline / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D014157:Transcription Factors; D014568:Urokinase-Type Plasminogen Activator; D013752:Tetracycline