Prevention of Acute Liver Failure in Rats with Reversibly Immortalized Human Hepatocytes

Kobayashi, Naoya; Fujiwara, Toshiyoshi; Westerman, Karen A.; Inoue, Yusuke; Sakaguchi, Masakiyo; Noguchi, Hirofumi; Miyazaki, Masahiro; Cai, Jiabing; Tanaka, Noriaki; Fox, Ira J.; Leboulch, Philippe

doi:10.1126/science.287.5456.1258

Cited by 321 publications

(175 citation statements)

References 19 publications

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“…17 The 2 basic types of human hepatocyte lines are those derived from human tumors 18,19 and those created by immortalizing human hepatocytes. [20][21][22] Tumor-derived line. One of the most developed BAL systems currently under trial, the ELAD system 23,24 (VITAGEN Inc, La Jolla, CA), uses the C3A cell line, a clonal derivative of the hepatoblastoma-based HepG2 cell line, which is reported to have a more highly differentiated hepatic phenotype than the HepG2 line.…”

Section: Human Hepatocyte Cell Linesmentioning

confidence: 99%

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Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Tsiaoussis

Newsome

Nelson

et al. 2001

Liver Transplantation

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Liver failure, notwithstanding advances in medical management, remains a cause of considerable morbidity and mortality in the developed world. Although bioartificial liver (BAL) support systems offer the potential of significant therapeutic benefit for such patients, many issues relating to their use are still to be resolved. In this review, these issues are examined in terms of the functions required, the cells of choice in such a system, and the most appropriate environment to optimize the function of such cells T he development of nonbiological systems to support critically ill patients with acute liver failure (ALF) that incorporate plasmapheresis, 1 charcoal hemoperfusion, 2 and ultrafiltration techniques 3 has not had a significant impact on survival. Consequently, hepatocytebased biological systems have attracted intense interest worldwide but have also generated most of the controversy. Uncertainty exists about the most suitable biological component and the risk for zoonoses and immune rejection in the host. In addition, the optimization of culture conditions and thus metabolic function of the biological component have not been systematically studied, although continuing improvements in these areas have rendered this therapeutic avenue in ALF more promising. To compound matters, the question of which aspects of hepatocyte metabolism in an artificial liver are required to sustain life and promote recovery remains largely unanswered, further limiting development. In this review, the biological substrate of such systems is critically examined and insights are provided into the ideal system.

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Section: Human Hepatocyte Cell Linesmentioning

confidence: 99%

“…The recent development of a reversibly immortalized cell line, NKNT-3, 22 has been heralded as a breakthrough for hepatocyte transplantation. The NKNT-3 line is produced by the retroviral transfection of normal primary human hepatocytes with SV40T flanked by LoxP recombination targets.…”

Section: Human Hepatocyte Cell Linesmentioning

confidence: 99%

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Tsiaoussis

Newsome

Nelson

et al. 2001

Liver Transplantation

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show abstract

“…5) and is commonly expressed in liver and other tissues (45) as an inflammatory cytokine that can also induce TNF-␣ (46). Studies with anti-MIF Ab demonstrate a protective effect in models of endotoxin-induced injury (47).…”

Section: Cytokinesmentioning

confidence: 99%

Reduced Early Alcohol-Induced Liver Injury in CD14-Deficient Mice

Yin

Bradford

Wheeler

et al. 2001

The Journal of Immunology

225

125

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Activation of Kupffer cells by gut-derived endotoxin is associated with alcohol-induced liver injury. Recently, it was shown that CD14-deficient mice are more resistant to endotoxin-induced shock than wild-type controls. Therefore, this study was designed to investigate the role of CD14 receptors in early alcohol-induced liver injury using CD14 knockout and wild-type BALB/c mice in a model of enteral ethanol delivery. Animals were given a high-fat liquid diet continuously with ethanol or isocaloric maltose-dextrin as control for 4 wk. The liver to body weight ratio in wild-type mice (5.8 ± 0.3%) was increased significantly by ethanol (7.3 ± 0.2%) but was not altered by ethanol in CD14-deficient mice. Ethanol elevated serum alanine aminotransferase levels nearly 3-fold in wild-type mice, but not in CD14-deficient mice. Wild-type and knockout mice given the control high-fat diet had normal liver histology, whereas ethanol caused severe liver injury (steatosis, inflammation, and necrosis; pathology score = 3.8 ± 0.4). In contrast, CD14-deficient mice given ethanol showed minimal hepatic changes (score = 1.6 ± 0.3, p < 0.05). Additionally, NF-κB, TGF-β, and TNF-α were increased significantly in wild-type mice fed ethanol but not in the CD14 knockout. Thus, chronic ethanol feeding caused more severe liver injury in wild-type than CD14 knockouts, supporting the hypothesis that endotoxin acting via CD14 plays a major role in the development of early alcohol-induced liver injury.

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“…However, the consequence of long-term T-Ag expression and the genetic stability of the cells have not been studied (Kobayashi et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Long-term controlled immortalization of a primate hepatic progenitor cell line after Simian virus 40 T-Antigen gene transfer

et al. 2004

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Hepatoblasts are bipotent progenitors of both hepatocytes and cholangiocytes. The lack of stable in vitro culture systems for such cells makes it necessary to generate liver progenitor cell lines by means of immortalization. In this study, we describe the long-term behaviour of a clone of simian foetal hepatic progenitor cells immortalized by Simian virus 40 (SV40) large T-antigen (T-Ag) flanked by loxP sites. Immortalization was associated with the reexpression of telomerase activity, which decreased at late passages (population doubling 120) after more than a year in culture. This decrease was concomitant to telomere shortening and karyotypic instability. However, the chromosomes carrying the p53 gene remained intact and long-term immortalized progenitor cells maintained contact inhibition and proliferative properties. They also displayed the features of a normal bipotent phenotype. We constructed a retroviral vector expressing an inducible Cre recombinase and transferred it into the immortalized progenitors. Activation of the Cre recombinase by 4-hydroxy-tamoxifen induced SV40 T-Ag excision, leading to the death of cells expressing Cre recombinase. Immortalized progenitors at late passages stopped growing and eventually disappeared after transplantation into the livers of immunocompromised mice. These cells provide a novel model to study hepatic differentiation and carcinogenesis.

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Prevention of Acute Liver Failure in Rats with Reversibly Immortalized Human Hepatocytes

Cited by 321 publications

References 19 publications

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Reduced Early Alcohol-Induced Liver Injury in CD14-Deficient Mice

Long-term controlled immortalization of a primate hepatic progenitor cell line after Simian virus 40 T-Antigen gene transfer

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