Generation of integration-free induced hepatocyte-like cells from mouse fibroblasts.
The ability to generate integration-free induced hepatocyte-like cells (iHeps) from somatic fibroblasts has the potential to advance their clinical application. Here, we have generated integration-free, functional, and expandable iHeps from mouse somatic fibroblasts. To elicit this direct conversion, we took advantage of an oriP/EBNA1-based episomal system to deliver a set of transcription factors, Gata4, Hnf1a, and Foxa3, to the fibroblasts. The established iHeps exhibit similar morphology, marker expression, and functional properties to primary hepatocytes. Furthermore, integration-free iHeps prolong the survival of fumarylacetoacetate-hydrolase-deficient (Fah(-/-)) mice after cell transplantation. Our study provides a novel concept for generating functional and expandable iHeps using a non-viral, non-integrating, plasmid-based system that could facilitate their pharmaceutical and biomedical application.
Department of Stem Cell Biology, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Jonghun
J
Kim
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Kee-Pyo
KP
Kim
Department of Stem Cell Biology, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Kyung Tae
KT
Lim
Department of Stem Cell Biology, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Seung Chan
SC
Lee
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Juyong
J
Yoon
REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany.
Guangqi
G
Song
Department of Stem Cell Biology, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Seon In
SI
Hwang
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.|University of Münster, Medical Faculty, Domagkstrasse 3, 48149 Münster, Germany.
Hans R
HR
Schöler
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.|REBIRTH Cluster of Excellence, Hannover Medical School, Hannover 30625, Germany.
Tobias
T
Cantz
Department of Stem Cell Biology, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.|KU Open-Innovation Center, Institute of Biomedical Science &Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Dong Wook
DW
Han
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics; D007621:Karyotyping; D053538:Keratin-18 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D050991:GATA4 Transcription Factor; D051538:Hepatocyte Nuclear Factor 1-alpha; D053538:Keratin-18; D012709:Serum Albumin; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D051543:Hepatocyte Nuclear Factor 3-gamma; D003577:Cytochrome P-450 Enzyme System; D006867:Hydrolases; C020156:fumarylacetoacetase