Hepatoblast-like progenitor cells derived from embryonic stem cells can repopulate livers of mice.
OBJECTIVE
Hepatocyte-like cells can be derived from pluripotent stem cells such as embryonic stem (ES) cells, but ES cell-derived hepatic cells with extensive capacity to repopulate liver have not been identified. We aimed to identify and purify ES cell-derived hepatoblast-like progenitor cells and to explore their capacity for liver repopulation in mice after in vitro expansion.


METHODS
Unmanipulated mouse ES cells were cultured under defined conditions and allowed to undergo stepwise hepatic differentiation. The derived hepatic cells were examined by morphologic, fluorescence-activated cell sorting, gene expression, and clonal expansion analyses. The capacities of ES cell-derived hepatic progenitor cells to repopulate liver were investigated in mice that were deficient in fumarylacetoacetate hydrolase (Fah) (a model of liver injury).


RESULTS
Mouse ES cells were induced to differentiate into a population that contained hepatic progenitor cells; this population included cells that expressed epithelial cell adhesion molecule (EpCAM) but did not express c-Kit. Clonal hepatic progenitors that arose from single c-Kit(-)EpCAM(+) cells could undergo long-term expansion and maintain hepatoblast-like characteristics. Enriched c-Kit(-)EpCAM(+) cells and clonally expanded hepatic progenitor cells repopulated the livers of Fah-deficient mice without inducing tumorigenesis.


CONCLUSIONS
ES cell-derived c-Kit(-)EpCAM(+) cells contain a population of hepatoblast-like progenitor cells that can repopulate livers of mice.
Li
Fuming
F
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Shanghai, China.
Liu
Pingyu
P
Liu
Changcheng
C
Xiang
Dao
D
Deng
Li
L
Li
Wenlin
W
Wangensteen
Kirk
K
Song
Jianguo
J
Ma
Yue
Y
Hui
Lijian
L
Wei
Lixin
L
Li
Lingsong
L
Ding
Xiaoyan
X
Hu
Yiping
Y
He
Zhiying
Z
Wang
Xin
X
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology*; D006867:Hydrolases / Q000235:genetics; D008107:Liver Diseases / Q000473:pathology* / Q000628:therapy*; D008115:Liver Regeneration; D051379:Mice; D008817:Mice, Mutant Strains; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D033581:Stem Cell Transplantation
D019009:Proto-Oncogene Proteins c-kit; D006867:Hydrolases; C020156:fumarylacetoacetase