Factors from Human Embryonic Stem Cell-derived Fibroblast-like Cells Promote Topology-dependent Hepatic Differentiation in Primate Embryonic and Induced Pluripotent Stem Cells

The future clinical use of embryonic stem cell (ESC)-based hepatocyte replacement therapy depends on the development of an efficient procedure for differentiation of hepatocytes from ESCs. Here we report that a high density of human ESC-derived fibroblast-like cells (hESdFs) supported the efficient...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-10, Vol.285 (43), p.33510-33519
Main Authors: Huang, Hsiang-Po, Yu, Chun-Ying, Chen, Hsin-Fu, Chen, Pin-Hsun, Chuang, Ching-Yu, Lin, Sung-Jan, Huang, Shih-Tsung, Chan, Wei-Hung, Ueng, Tzuu-Huei, Ho, Hong-Nerng, Kuo, Hung-Chih
Format: Article
Language:English
Subjects:
Activins - metabolism
Animals
Cell Biology
Cell Differentiation
Cell Differentiation - physiology
Developmental Biology
Embryonic Stem Cell
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
Fibroblast Growth Factor 2 - metabolism
Fibroblasts - cytology
Fibroblasts - metabolism
Haplorhini
Hepatocyte
Hepatocytes - cytology
Hepatocytes - metabolism
Humans
Induced Pluripotent Stem Cell (iPSC)
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Liver
Liver - cytology
Liver - metabolism
Mice
Primates
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Summary:The future clinical use of embryonic stem cell (ESC)-based hepatocyte replacement therapy depends on the development of an efficient procedure for differentiation of hepatocytes from ESCs. Here we report that a high density of human ESC-derived fibroblast-like cells (hESdFs) supported the efficient generation of hepatocyte-like cells with functional and mature hepatic phenotypes from primate ESCs and human induced pluripotent stem cells. Molecular and immunocytochemistry analyses revealed that hESdFs caused a rapid loss of pluripotency and induced a sequential endoderm-to-hepatocyte differentiation in the central area of ESC colonies. Knockdown experiments demonstrated that pluripotent stem cells were directed toward endodermal and hepatic lineages by FGF2 and activin A secreted from hESdFs. Furthermore, we found that the central region of ESC colonies was essential for the hepatic endoderm-specific differentiation, because its removal caused a complete disruption of endodermal differentiation. In conclusion, we describe a novel in vitro differentiation model and show that hESdF-secreted factors act in concert with regional features of ESC colonies to induce robust hepatic endoderm differentiation in primate pluripotent stem cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.122093