Liver organoid model to test drug-induced liver fibrosis and other liver diseases

Chronic liver diseases, such as alcoholic liver disease, non-alcoholic fatty liver disease and viral hepatitis, lead to liver fibrosis and subsequent liver cirrhosis.  According to WHO, liver cirrhosis accounts for 1.8% of all deaths in Europe, causing around 170.000 deaths/year, with a higher prevalence in east and west Europe. However, in terms of fibrosis, no pharmacological agent has been approved for routine use in a clinical context. In addition, no good in vitro models of fibrosis exist that can predict a fibrotic potential of a compound.Current models for in vitro fibrosis consist of simple mono-layer cultures of rodent hepatic stellate cells (HSC) the key players in fibrosis but ignoring the role of other events and cells such as hepatocyte injury. Hence, there is a particular need for assays suitable for identifying human pro-fibrotic and anti-fibrotic compounds, taking into account not only the direct but also the indirect activation of HSCs. 

The Liver Cell Biology research group (LIVR) of the VUB developed mouse and human hepatic spheroid cultures to detect drug-induced liver fibrosis. These organoids cultured in 96-well plates consist of human hepatocytes and primary HSCs, primary mouse hepatocytes and HSCs or primary mouse hepatocyte/HSC/Kupffer cell/liver sinusoidal endothelial cells which have been characterized for their competence and functionality for up to 14-21 days. A European patent is being granted on these spheroid co-cultures, published as EP3152296.  

These spheroid cultures can pinpoint drug-induced hepatic injury but also drug-induced liver fibrosis upon single and repeated exposures of compounds. The size of the test unit (1 well in 96-well plate) allows for screening of multiple compounds and different conditions. Currently, these spheroid cultures are being tested for the detection of other liver diseases such as steatosis, phospholipidosis, cholestasis and cancer.

PCT/EP2015/062551 “HUMAN HEPATIC 3D CO-CULTURE MODEL AND USES THEREOF”; The claimed invention describes “a 3D co-culture of hepatic cells and stellate cells in which the stellate cells are in excess of the hepatocytes” and that “the cultures are used for the screening of pro- or anti-fibrotic compounds”