title: Small Molecules Facilitate Single Factor-Mediated Hepatic Reprogramming.
abstract: Recent studies have shown that defined factors could lead to the direct conversion of fibroblasts into induced hepatocyte-like cells (iHeps). However, reported conversion efficiencies are very low, and the underlying mechanism of the direct hepatic reprogramming is largely unknown. Here, we report that direct conversion into iHeps is a stepwise transition involving the erasure of somatic memory, mesenchymal-to-epithelial transition, and induction of hepatic cell fate in a sequential manner. Through screening for additional factors that could potentially enhance the conversion kinetics, we have found that c-Myc and Klf4 (CK) dramatically accelerate conversion kinetics, resulting in remarkably improved iHep generation. Furthermore, we identified small molecules that could lead to the robust generation of iHeps without CK. Finally, we show that Hnf1α supported by small molecules is sufficient to efficiently induce direct hepatic reprogramming. This approach might help to fully elucidate the direct conversion process and also facilitate the translation of iHep into the clinic.
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Lim
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea; Department of Advanced Translational Medicine, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Seung Chan
authors.initials: SC
authors.lastname: Lee
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 and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Kee-Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Guangqi
authors.initials: G
authors.lastname: Song
authors.affiliation: Laboratory of Stem Cell Biology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: An
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Laboratory of Stem Cell Biology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jang
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Jonghun
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Oh
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea; Department of Advanced Translational Medicine, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Seon In
authors.initials: SI
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Kinarm
authors.initials: K
authors.lastname: Ko
authors.affiliation: College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Amar Deep
authors.initials: AD
authors.lastname: Sharma
authors.affiliation: Laboratory of Stem Cell Biology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kim
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: Lijian
authors.initials: L
authors.lastname: Hui
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Department of Gastroenterology, Hepatology, and Endocrinology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Cantz
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea; Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Medical Faculty, University of Münster, Domagkstrasse 3, 48149 Münster, Germany.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea; KU Open-Innovation Center, Institute of Biomedical Science & Technology, Konkuk University, Seoul 143-701, Republic of Korea; Department of Advanced Translational Medicine, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea. Electronic address: dwhan@konkuk.ac.kr.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Han
keywords: MET; conversion kinetics; direct conversion; induced hepatocytes