Development of a human induced pluripotent stem cell-derived 3D liver NAFLD culture model.

Non-alcoholic fatty liver disease (NAFLD) affects 1 billion people worldwide and is currently the most prevalent form of chronic liver disease. In the more severe form it can lead to fibrosis (scar tissue) and inflammation which can lead to complications such as liver cancer. To study NAFLD, experiments are performed in rodents as well as cellular in vitro models, but a representative model where fibrosis onset can be related to humans has yet to be established. This lack of an adequate model is one of the reasons why there are currently no NAFLD therapies available in the clinic. The aim of this project is to generate a well characterized in vitro human NAFLD model consisting of (induced pluripotent) stem cell-derived liver cells. We will establish 3D cultures and induce NAFLD by exposing them to medium rich in fat and sugar. Next, we will use miniaturized bioreactors to mimic the blood flow and the recruitment of inflammatory cells. We will validate the novel NAFLD model by using potential anti-NAFLD therapeutics and we will compare the new model with established mouse models of NAFLD and with patient data. Finally, we will evaluate whether the new in vitro NAFLD model can respond to medication currently in clinical trials for NAFLD and liver fibrosis. The outcome of the project will be a stem cell-derived human in vitro culture model that can be used to discover new pathways and molecules involved in NAFLD that could lead to innovative therapeutic approaches.