Human liver slices as an in vitro model to study toxicity-induced hepatic stellate cell activation in a multicellular milieu

Introduction: Hepatic stellate cell (HSC) activation is a key event in wound healing as well as in fibrosis development in the liver. Previously we developed a technique to induce HSC activation in slices from rat liver. Although this model provides a physiologic, multicellular milieu that is not present in current in vitro models it might still be of limited predictive value for the human situation due to species-differences. Therefore, we now aimed to evaluate the applicability of human liver slices for the study of HSC activation. Method: Liver slices (8 mm diameter, 250 mu m thickness) were generated from human liver tissue and incubated for 3 or 16 h with 0-15 mu l of carbon tetrachloride (CCl4) after which ATP-content and expression levels of HSC (activation) markers was determined. Results: Human liver slices remained viable during incubation as shown by constant ATP levels. Incubation with CCl4 caused a dose-dependent decrease in viability and an increase in mRNA expression of the early HSC activation markers HSP47 and alpha beta-crystallin, but not the late markers for HSC activation, alpha SMA and pro-collagen 1a1. Synaptophysin mRNA expression remained constant during incubation with or without CCl4, indicating a constant number of HSC in the liver slices. Conclusion: We developed a technique to induce early toxicity-induced HSC activation in human liver slices. This in vitro model provides a multicellular, physiologic milieu to study mechanisms underlying toxicity-induced HSC activation in human liver tissue. (c) 2006 Elsevier Ireland Ltd. All rights reserved.