Hepatocytes - Toxicity analysis in expanded upcyte® liver cells on Nanion’s CardioExcyte 96
Drug induced hepatic toxicity is one of the main reasons for regulatory actions and market withdrawals in the last 50 years . In Europe and the USA, the major cause of acute liver failure is indeed Drug Induced Liver Injury (DILI) . Current existing in vitro models employed to predict DILI mostly focus on hepatocytes. Other cell types of the liver, such as liver sinusoidal endothelial cells (LSECs), are often overlooked. It is thus questionable whether, hepatotoxicity can be sufficiently predicted by analyzing hepatocytes only. LSECs are highly specialized endothelial cells forming the hepatic sinusoidal wall. Besides their high endocytic potential, LSECs have been demonstrated to markedly contribute to liver homeostasis, immunity, and may partially explain unexpected hepatotoxicity of selected drug candidates. Several reports in the literature have highlighted a high sensitivity of LSECs towards hepatotoxic drugs . It has been suggested that LSECs act as an early direct target for acetaminophen (paracetamol) induced toxicity, causing early swelling and loss of uptake activity and fenestrations before effects on hepatocytes are observed . LSECs are further important cellular targets during sinusoidal obstruction syndrome (a distinctive and potentially fatal form of hepatic injury that occurs predominantly, if not only, after drug or toxin exposure). The use of primary LSECs for comprehensive in vitro studies is compromised by poor cell yields, rapid dedifferentiation, contamination with other endothelial cells, and limited proliferation after isolation . In this study upcyte® LSECs have been developed as a complementary tool to predict hepatotoxicity, uptake and drug interactions. In addition to conventional toxicity readouts such as ATP levels, upcyte® LSECs have been successfully tested using an impedance based system.