Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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Induction and High Density Culture of Human Hepatoblasts from Fetal Hepatocytes with Suppressing Transformation
Akifumi KiyotaTaku MatsushitaRyuichi Ueoka
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2007 Volume 30 Issue 12 Pages 2308-2311

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Abstract

It is well known that it would be important to cultivate human hepatocytes of about 1010 cells at a high cell density, about 1×107 cells/cm3, in the bioreactor for the development of bioartificial liver. However, since primary human hepatocytes lack an ability to proliferate in vitro, it is essential to establish a culture method for the proliferation of normal human hepatic stem cells as a cell source. In this study, it was found that human hepatoblasts, a kind of hepatic stem cells, were induced from human fetal hepatocytes while keeping the ability of proliferation by the treatment of 1mM sodium butyrate (SB) for 12 d of culture. The transformation of hepatoblasts was evaluated by abnormal prothrombin (PIVKA-II) assay, which is a clinical marker for hepatocellular carcinoma. The PIVKA-II production rate of the cells was suppressed to the normal level under 1 mM SB. The cells including hepatoblasts under 1 mM SB attached to the porous hydroxyapatite carriers and proliferated to a high cell density of about 1×107 cells/cm3 in the carriers. The liver-specific function, cytochrome P450 3A4 activity (4.2 pmol/mg protein/min) of the cells in the carriers under 1 mM SB was comparable to that of primary human hepatocytes. Ammonia metabolizing activity (0.21 μmol/106 cells/h) of the cells was also comparable to that of porcine hepatocytes used in the bioartificial liver. The PIVKA-II production rate of the cells in the carrier was suppressed to the normal level. These results suggested that induction of human hepatoblasts from fetal hepatocytes by the treatment of 1mM SB and proliferation of the cells at a high cell density using hydroxyapatite carriers should be one of the more promising culture methods for bioartificial liver developments.

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© 2007 The Pharmaceutical Society of Japan
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