Non-Alcoholic Fatty Liver Disease (NAFLD) ranges from simple steatosis to liver inflammation and/or fibrosis, and it is recognized as a risk factor for liver failure and hepatocellular carcinoma. Despite its high prevalence (25-30% in the general population), specific therapy is not available and drug discovery has been hampered by the lack of a suitable system that encompasses all the different aspects of NAFLD. Animal models are widely used to study NAFLD, but they fail to fully reproduce the human pathophysiology while in vitro models are currently not available due to the difficulty to grow primary hepatic cells. In addition, current culture systems do not allow for long term studies, and, most importantly, do not include the diversity of cell types consequent to hepatocyte damage.
This proposal aims to develop a novel platform for modelling the different features of NAFLD using human Induced Pluripotent Stem Cells (hIPSCs). For that, I will take advantage of a culture system that I recently established, consisting of 3D (co)-cultures of hepatocytes, cholangiocytes, macrophages and stellate cells derived from hIPSCs. I will first demonstrate that NAFLD can be modelled by metabolic stimuli in normal hIPSCs or hIPSCs with NAFLD-associated polymorphisms. This will allow to demonstrate the interest of this new platform to study mechanisms of hepatocytes steatosis and lipotoxicity including the processes influencing the inflammatory and the fibrotic response associated with progression of NAFLD. This system will be further validated by direct comparison with the hepatic transcriptome of NAFLD patients. Finally, the last step of this program will establish the interest of this platform for drug screening and target validation. The possibility to model NAFLD using hIPSCs holds great potential in providing a unique alternative to animal models and an attractive approach for the discovery of urgently needed novel therapeutic targets.
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Segeritz CP et al. (2018). hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α 1-antitrypsin deficiency. Journal of Hepatology 69(4): 851-860. doi:10.1016/j.jhep.2018.05.028