title: Direct reprogramming of human fibroblasts to functional and expandable hepatocytes.
abstract: 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.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ludi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: He
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yao
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cen
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Changcheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Hu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Lai
authors.affiliation: Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Zhenlei
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ma
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Pan
authors.affiliation: Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Hohhot 010021, China; Department of Laboratory Medicine and Pathology, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA; Hepatoscience Incorporation, 4062 Fabian Way, Palo Alto, CA 94303, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: ljhui@sibcb.ac.cn.
authors.forename: Lijian
authors.initials: L
authors.lastname: Hui
mesh_terms: D000328:Adult; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D003208:Concanavalin A; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000378:metabolism; D008658:Inactivation, Metabolic; D017093:Liver Failure / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D003208:Concanavalin A; D006867:Hydrolases; C020156:fumarylacetoacetase