Document Detail

Survival of liver failure pigs by transplantation of reversibly immortalized human hepatocytes with Tamoxifen-mediated self-recombination.
MedLine Citation:
PMID:  17434229     Owner:  NLM     Status:  MEDLINE    
BACKGROUND/AIMS: Hepatocyte transplantation and bioartificial liver treatment are attractive alternatives to liver transplantation. The availability of well-characterized human hepatocyte lines facilitates such cell therapies. METHODS: Human hepatocytes were immortalized with a retroviral vector SSR#197 expressing catalytic subunit of human telomerase reverse transcriptase (hTERT) and enhanced green fluorescent protein (EGFP) cDNAs flanked by a pair of loxP recombination targets. Then, Tamoxifen-dependent Cre recombinase was expressed in SSR#197-immortalized hepatocytes. Cre/LoxP recombination was performed in the established cells by simple exposure to 500 nM Tamoxifen for a week. Then, the reverted population of the cells was recovered by EGFP-negative cell sorting and characterized in vitro and in vivo using a pig model of acute liver failure (ALF) induced by d-galactosamine (0.5 g/kg) injection. RESULTS: A human hepatocyte cell line 16T-3 was established. Reverted 16-T3 cells showed the increased expression of hepatic markers in association with enhanced levels of transcriptional factors. Compared to normal human hepatocytes, albumin production and lidocaine-metabolizing activities of reverted 16-T3 cells were 0.32 and 0.50-fold, respectively. Transplantation of reverted 16T-3 cells significantly prolonged the survival of ALF pigs. CONCLUSIONS: Here we demonstrate the usefulness of Cre/LoxP -mediated reversible immortalization of human hepatocytes with Tamoxifen-mediated self-recombination.
Toshinori Totsugawa; Chen Yong; Jorge David Rivas-Carrillo; Alejandro Soto-Gutierrez; Nalú Navarro-Alvarez; Hirofumi Noguchi; Teru Okitsu; Karen A Westerman; Michinori Kohara; Michael Reth; Noriaki Tanaka; Philippe Leboulch; Naoya Kobayashi
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Publication Detail:
Type:  Journal Article     Date:  2007-03-15
Journal Detail:
Title:  Journal of hepatology     Volume:  47     ISSN:  0168-8278     ISO Abbreviation:  J. Hepatol.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-06-04     Completed Date:  2007-09-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  England    
Other Details:
Languages:  eng     Pagination:  74-82     Citation Subset:  IM    
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan.
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MeSH Terms
Biological Markers / analysis
Cell Line, Transformed / chemistry,  cytology,  transplantation*
Hepatocytes / chemistry,  drug effects,  transplantation*
Integrases / genetics
Liver Failure / pathology,  surgery*
Recombination, Genetic
Retroviridae / genetics
Sus scrofa
Tamoxifen / pharmacology
Treatment Outcome
Reg. No./Substance:
0/Biological Markers; 10540-29-1/Tamoxifen; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases

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