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ToxSci Advance Access published online on February 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi127
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received December 4, 2004
Accepted February 15, 2005

In Vitro Toxicology

Precision-cut liver slices as a new model to study toxicity-induced hepatic stellate cell activation in a physiologic milieu

Marja van de Bovenkamp 1*, Geny M. M. Groothuis 1, Annelies L. Draaisma 1, Marjolijn T. Merema 1, Judith I. Bezuijen 1, Marit J. van Gils 1, Dirk K. F. Meijer 1, Scott L. Friedman 2, and Peter Olinga 1

1 Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, Groningen, The Netherlands
2 Mount Sinai School of Medicine, Division Liver Diseases, New York, NY

* To whom correspondence should be addressed.
Marja van de Bovenkamp, E-mail: M.van.de.Bovenkamp{at}rug.nl


  Abstract

Hepatic stellate cell (HSC) activation is a key event in the natural process of wound healing as well as in fibrosis development in liver. Current in vitro models for HSC activation contribute significantly to the understanding of HSC-biology and fibrogenesis but still fall far short of recapitulating in vivo intercellular functional and anatomic relationships. In addition, when cultured on uncoated plastic, HSC spontaneously activate, which makes HSC activation difficult to regulate or analyze. We have examined whether the use of precision-cut liver slices might overcome these limitations. Liver slices (8mm diameter, 250µm thickness) were generated from normal rat liver and incubated for 3 or 16 hours with increasing doses of carbon tetrachloride (CCl4). Rat liver slices remained viable during incubation, as shown by minimal enzyme leakage. Expression of markers for HSC-activation and the onset of fibrogenesis in the liver slices was studied using real-time PCR and Western blotting. In unstimulated liver slices, mRNA and protein levels of desmin, heat shock protein 47, and {alpha}B-crystallin remained constant, indicating quiescence of HSC, whereas Krüppel-like factor 6 expression was increased. In contrast, incubation with CCl4 led to a time and dose-dependent increase in mRNA expression of all markers and an increased {alpha}B-crystallin protein expression. In conclusion, we have developed a technique to induce activation of quiescent HSC in rat liver slices. This model enables to study toxicity-induced HSC activation within a physiological milieu not only in animal but ultimately also in human tissue and could contribute to the reduction of animal experiments.


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