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

IntroductionHepatic 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.MethodLiver slices (8 mm diameter, 250 μm thickness) were generated from human liver tissue and incubated for 3 or 16 h with 0–15 μl of carbon tetrachloride (CCl4) after which ATP-content and expression levels of HSC (activation) markers was determined.ResultsHuman 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 αB-crystallin, but not the late markers for HSC activation, αSMA 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.ConclusionWe 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.