Development of a diet-induced disease-mimicking in vitro model of non-alcoholic steatohepatitis (NASH/ fibrosis)

Abstract: Non-alcoholic steatohepatitis (NASH) is a severe condition that is expected to be the leading cause of liver transplantations in the coming years. Importantly, no effective treatments are currently on the market that are able to either halt or reverse fibrosis in patients. NASH is characterized by induction of steatosis in hepatocytes, resulting in activation of hepatic stellate cells (HSC). Activated HSC start depositing excessive amounts of collagen in the liver. The resulting fibrosis impairs the function of the liver, eventually leading to organ dysfunction and an increased risk on hepatocellular carcinoma.
Anti-fibrotic drug development is hampered by the lack of knowledge of disease mechanisms, relevant biomarkers and predictive in vivo and in vitro models. Therefore, we developed a disease-mimicking in vitro model which closely resembles the pathophysiology of liver fibrosis.

The model is based on 3D co-culture of human stem cell-derived hepatocytes and human stellate cells in a multi-spheroid scaffold. Steatosis is induced by applying fatty acids, which activates human stellate cells. Collagen and α-smooth muscle actin are used as read-outs. The next goal will be to mimic patient variability in vitro by using iPSC’s from various individuals. The final goal is to develop a population-on-a-chip model which can be used for drug development and a preclinical precision medicine approach.