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First published on February 10, 2006; DOI: 10.1124/dmd.105.007708

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Received for publication October 4, 2005.
Revised January 9, 2006.
Accepted for publication February 3, 2006.

Gene expression in human hepatocytes in suspension after isolation is similar to the liver of origin, is not affected by hepatocyte cold storage and cryopreservation, but is strongly changed after hepatocyte plating

Lysiane Richert 1*, Michael J Liguori 2, Catherine Abadie 1, Bruno Heyd 3, Georges Mantion 3, Nermin Halkic 4, Jeffrey F Waring 2

1 Laboratoire de Biologie Cellulaire, UFR SMP 2 Abbott Laboratories 3 Centre de Transplantation Hepatique 4 Centre Hospitalier Universitaire Vaudois

* Address correspondence to: E-mail: lrichert{at}univ-fcomte.fr

Abstract

Isolated primary human hepatocytes are a well-accepted system for evaluating pharmacological and toxicological effects in humans. However, questions remain regarding how culturing impacts the liver-specific functions of the hepatocytes. In addition, cryopreservation could also potentially affect the differentiation state of the hepatocytes. The first aim of the present study was to compare gene expression in freshly isolated primary hepatocytes to that of the liver of origin, and to evaluate the expression changes occurring following cryopreservation/thawing, both when maintained in suspension and after plating. The second aim of the present study was to evaluate gene expression in hepatocytes following cold storage of suspensions up to 24h, compared to freshly isolated hepatocytes in suspension. Our results show that the gene expression in freshly isolated human hepatocytes in suspension after isolation is similar to that of the liver of origin. Furthermore, gene expression in primary human hepatocytes in suspension is not affected by hepatocyte cold storage and cryopreservation. However, the gene expression is profoundly affected in monolayer cultures after plating. Specifically, gene expression changes were observed in cultured relative to suspensions of human hepatocytes that are involved in cellular processes such as phase I/II metabolism, basolateral and canicular transport systems, fatty acid and lipid metabolism, apoptosis, and proteasomal protein recycling. An oxidative stress response may be partially involved in these changes in gene expression. Taken together, these results may aide in the interpretation of data collected from human hepatocyte experiments and suggest additional utility for cold storage and cryopreservation of hepatocytes.


Key words: enzyme induction, gene regulation, genomics, glucuronidation, hepatic transport, hepatocytes, human CYP enzymes, isolated hepatocytes, microarrays


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