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Stem Cell Reports. 2018 May 8;10(5):1522-1536. doi: 10.1016/j.stemcr.2018.03.002. Epub 2018 Mar 29.

Direct Conversion of Mouse Fibroblasts into Cholangiocyte Progenitor Cells.

Author information

1
Department of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
2
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
3
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 04056, Republic of Korea.
4
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
5
Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
6
Department of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
7
Department of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; KU Open-Innovation Center, Institute of Biomedical Science & Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea; Department of Advanced Translational Medicine, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. Electronic address: dwhan@konkuk.ac.kr.

Abstract

Disorders of the biliary epithelium, known as cholangiopathies, cause severe and irreversible liver diseases. The limited accessibility of bile duct precludes modeling of several cholangiocyte-mediated diseases. Therefore, novel approaches for obtaining functional cholangiocytes with high purity are needed. Previous work has shown that the combination of Hnf1β and Foxa3 could directly convert mouse fibroblasts into bipotential hepatic stem cell-like cells, termed iHepSCs. However, the efficiency of converting fibroblasts into iHepSCs is low, and these iHepSCs exhibit extremely low differentiation potential into cholangiocytes, thus hindering the translation of iHepSCs to the clinic. Here, we describe that the expression of Hnf1α and Foxa3 dramatically facilitates the robust generation of iHepSCs. Notably, prolonged in vitro culture of Hnf1α- and Foxa3-derived iHepSCs induces a Notch signaling-mediated secondary conversion into cholangiocyte progenitor-like cells that display dramatically enhanced differentiation capacity into mature cholangiocytes. Our study provides a robust two-step approach for obtaining cholangiocyte progenitor-like cells using defined factors.

KEYWORDS:

Notch signal; cholangiocyte progenitor cells; direct conversion; hepatic stem cells

PMID:
29606616
PMCID:
PMC5995161
DOI:
10.1016/j.stemcr.2018.03.002
[Indexed for MEDLINE]
Free PMC Article

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