Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes.
Severe acute liver failure, even when transient, must be treated by transplantation and lifelong immune suppression. Treatment could be improved by bioartificial liver (BAL) support, but this approach is hindered by a shortage of human hepatocytes. To generate an alternative source of cells for BAL support, we differentiated mouse embryonic stem (ES) cells into hepatocytes by coculture with a combination of human liver nonparenchymal cell lines and fibroblast growth factor-2, human activin-A and hepatocyte growth factor. Functional hepatocytes were isolated using albumin promoter-based cell sorting. ES cell-derived hepatocytes expressed liver-specific genes, secreted albumin and metabolized ammonia, lidocaine and diazepam. Treatment of 90% hepatectomized mice with a subcutaneously implanted BAL seeded with ES cell-derived hepatocytes or primary hepatocytes improved liver function and prolonged survival, whereas treatment with a BAL seeded with control cells did not. After functioning in the BAL, ES cell-derived hepatocytes developed characteristics nearly identical to those of primary hepatocytes.
Soto-Gutiérrez
Alejandro
A
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Kobayashi
Naoya
N
Rivas-Carrillo
Jorge David
JD
Navarro-Alvarez
Nalu
N
Zhao
Debiao
D
Zhao
Debaio
D
Okitsu
Teru
T
Noguchi
Hirofumi
H
Basma
Hesham
H
Tabata
Yashuhiko
Y
Chen
Yong
Y
Tanaka
Kimiaki
K
Narushima
Michiki
M
Miki
Atsushi
A
Ueda
Tadayoshi
T
Jun
Hee-Sook
HS
Yoon
Ji-Won
JW
Lebkowski
Jane
J
Tanaka
Noriaki
N
Fox
Ira J
IJ
D028341:Activins / Q000502:physiology; D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000502:physiology*; D017690:Cell Transplantation / Q000379:methods / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000502:physiology* / Q000637:transplantation*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D017114:Liver Failure, Acute / Q000628:therapy*; D019164:Liver, Artificial; D051379:Mice; D023421:Models, Animal
C422405:activin A; D016222:Fibroblast Growth Factor 2; D028341:Activins; D017228:Hepatocyte Growth Factor