Microphysiological systems for studying the functions and interactions of the human liver, gut and immune system
Lecturer : Dr Tomasz Kostrzewski, Director of Biology, CN Bio Innovations Ltd.
Microphysiological systems (MPS), also known as organ-on-chips, are small scale in vitro cell cultures which mimic facets of tissue or organ level function. MPS frequently utilise primary human cells, often cultured in 3D, to obtain highly functional, physiologically relevant models. MPS can be utilized alone, but can also be connected through fluidic circuits to create advanced multi-MPS that can model the interactions between organ systems, allowing greater analysis of molecular pathways and disease mechanisms.
Most current in vitro liver models are simple mono-cultures of hepatocytes or use hepatic cell lines and do not have the complexity to analyse the interactions between different tissue types and determine how these interactions drive specific pathologies. We have developed a novel system for the in vitro culture of hepatocytes in a perfused three-dimensional format, with/without a separate co-culture allowing interactions to be studied with a second MPS. The model of the human liver contains multiple primary cell types, which can be cultured together for several weeks and maintain their phenotype and metabolic activity. This liver model can be used for DMPK, toxicology or disease modelling applications. Using the same perfused MPS platform, we combined this liver model with a culture of Caco-2 cells cultured on a transwell to form an epithelial gut barrier. Xenobiotics were dosed into the gut and observed to be absorbed across the epithelia before being taken up by the liver and metabolized, mimicking human ADME on the MPS platform. Finally, the liver contains a diverse collection of innate and adaptive immune cells which play a key role in nearly all hepatic diseases. Therefore, we also generated a liver-adaptive immune model, with PBMCs cultured in transwells and stimulated to produce a range of cytokines, including IFNγ. The presence of stimulated PBMCs caused hepatocytes to downregulate hepatic functions and induce an innate immune response against a model viral infection.
The MPS platform provides a tool to study in greater detail the key interactions between the gut, the liver and the immune system that drive pathologies including steatohepatitis, hepatocellular carcinoma and viral hepatitis.