RGM.20.011 – Modeling the dietary impact on health with engineered human liver microtissues

Route: Regenerative medicine: game changer moving to broad areas of application

Cluster question: 101 Can we model the human body and use smart technologies for health, nutritional, and toxicity research, drastically reducing the use of laboratory animals at the same time?

Better model system are urgently needed to study the impact of diet, nutrients and toxins on human health. This is particularly relevant in the light of grown health impact of overweight and obesity in modern society. Animal models are insufficient for this as they fail to recapitulate human-specific and individual-specific aspects in particular for obesity-related fatty liver disease. Patient-derived human-induced stem cells (iPSCs) offer great promise for diagnostics and personalized medicine. The induction and maintenance of the mature state of differentiation of iPSC-derived liver hepatocytes essential for human-relevant disease models, remain a major roadblock. The biomechanical and biochemical properties of the liver extracellular matrix (ECM) play a critical role in stem cell proliferation and hepatocyte differentiation. The underlying mechanism involved in full hepatocyte maturation remains largely elusive, but the biomechanics of the ECM, dynamical cell-cell and cell-ECM interactions, and growth factor signaling appear critical to the development of fully functional hepatocytes. So far, animal-derived matrices have been used to differentiate and maintain the hepatocyte-like cells in-vitro. These matrices inherently include serious limitations, prohibiting full liver cell differentiation. Our aim is to improve iPSC hepatocyte differentiation to be employed in liver disease modelling and personalized medicine. We will develop programmable soft materials for efficient and reproducible differentiation of hepatocytes. We intent to use these novel matrices in a microfluidic-chip to create three-dimensional multi-cellular liver models. These liver microtissues will be fully characterized to replicate critical features of normal and diseased liver tissue for personalized assessments eliminating the need for animal models. We will implement these engineered liver disease models for therapeutic drug discovery for ultimate patient treatment such as fatty liver disease.

Keywords

disease models, drug discovery and safety, iPSC technology, Liver, Organ-on-a-chip, programmable matrices

Other organisations

Eindhoven University of Technology (TU/e), Erasmus Medical Center (EMC), Netherlands Forensic Institute, Netherlands Organisation for Applied Scientific Research (TNO), Radboud Universiteit Nijmegen (RU), Technische Universiteit Delft (TUD), Universiteit Twente (UT), University of Applied Science Utrecht

Submitter

Organisation Universiteit Leiden (LEI)
Name Prof. dr. B. (Bob) van de Water
E-mail b.water@lacdr.leidenuniv.nl
Website https://www.universiteitleiden.nl/en/science/drug-research/drug-discovery-and-safety/cancer-therapeutics-and-drug-safety