Research

human liver model, bile formation and flow, cholestasis, iPSC, hepatocyte plate, ABC transporters

Interests

Bile formation and flow from the liver across the canalicular membrane and into the biliary tree is necessary for dietary fat absorption from the gut. It is also a major pathway for elimination of toxins and metabolic waste products. ATP Binding Cassette transporters are key to bile flow from the liver hepatocytes. Mutations in these transporters cause cholestasis and a range of secondary pathologies, from gallstones to liver failure in childhood. They are also common off-targets of therapeutic drugs, a major cause of failure of drugs in the pipeline due to the inadequacy of animal models to replicate the human drug-induced liver injury. Recently, it has become important to study these transporters as a system in a relevant cell-type. We have therefore developed a differentiation protocol for human hepatocytes from induced-pluripotent stem cells. The cellular ultrastructure of these induced-hepatocytes (iHEPs) is similar to liver and they produce albumin and express CYP3A4 important for xenobiotic detoxification. Importantly, the iHEPs make and transport bile into canaliculi formed between cells. We can also mimic cholestasis by application of known cholestatic drugs or by feeding excess bile acids. RNAseq analyses has identified the early markers of inflammation generated by the iHEPs in response to cholestasis and also the adaptive pathways triggered in response (manuscripts in preparation). We aim to use these human iHEPs to model human disease and to develop an accurate test bed for drugs that cause drug-induced liver injury. The first description of the model’s utility is described in Mazza et al Nat Comms 2024 where it was used to demonstrate the control of MRP2 (ABCC2) function by phosphorylation.

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