Format

Send to

Choose Destination
Cell Rep. 2016 Apr 26;15(4):814-829. doi: 10.1016/j.celrep.2016.03.071. Epub 2016 Apr 14.

Small Molecules Facilitate Single Factor-Mediated Hepatic Reprogramming.

Author information

1
Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
2
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.
3
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
4
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
5
Department of Gastroenterology, Hepatology, and Endocrinology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany.
6
Laboratory of Stem Cell Biology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
7
College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
8
Department of Biochemistry, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
9
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.
10
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.
11
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.

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.

KEYWORDS:

MET; conversion kinetics; direct conversion; induced hepatocytes

PMID:
27149847
DOI:
10.1016/j.celrep.2016.03.071
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center