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Project

Robotized Human Liver-Mimic 3D Model Platform for Efficient NAFLD and DILI Compound Screening

We propose to develop a fully automated all-induced pluripotent stem cell (iPSC)-3D- hepatic maturation hydrogel (HepMAT) liver model that can be used to create liver steatosis, inflammation and liver fibrosis, as seen in non-alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) suitable for development of drugs against this currently untreatable and very common disease. In addition, the platform will allow to evaluate the toxic effects of drugs on the liver (drug induced liver injury (DILI), the premier cause for drug failure at late stage drug development and post-marketing. The platform is based on novel technologies developed over the last 5 years allowing the creation of hepatocytes from iPSCs that display drug toxicity prediction as well as and drug metabolizing capacities similar to those of primary human hepatocytes (PHHs); and the creation of a unique, fully defined hydrogel-based 3D culture system containing iPSC-hepatocytes, as well as PSC-endothelium, -stellate cells and -macrophages, that can respond to inflammatory, steatotic and fibrogenic triggers in a very robust manner (termed HepMat cultures). In this C3 grant, these 3D all-iPSC-3DHepMAT liver cultures will be miniaturized and robotized, and validated/benchmarked in house for their suitability to create NAFLD/NASH-like disease models suitable for testing drugs against NAFLD/NASH as well as to identify with high specificity and DILI causing chemicals. The unique selling points of the model is (1) that it does not suffer from inter-donor and inter batch variability, which is unavoidable when using primary liver cells (as in the service offerings of our competitors); and (2) the system can be engineered with fluorophore cassettes allowing high content imaging of time-dependent, cell and stress pathway-specific effects of drugs and metabolic changes.
Date:1 Jan 2021 →  31 Dec 2022
Keywords:Induced pluripotent stem cells, 3D liver model, NAFLD/NASH, DILI, automation
Disciplines:Stem cell biology