The potential of human iPSC-derived hepatocytes as an in vitro tool to characterize drug hepatotoxicity

抄録

Drug-induced liver injury (DILI) remains a burden to the public, the pharmaceutical industry and regulators. Not only do we generally lack clear mechanisms that can explain the injury, but the manifestations of DILI are diverse, they are difficult to diagnose, and also they can take weeks or even months to develop. Whilst there are few good animal models of DILI, there are similarly few good in vitro models at present. Therefore, we believe that it is important that we understand what our in vitro/in vivo models are fit for as well as their limitations. Otherwise, model development will not be a rational scientific exercise. This talk will explore the challenging area of liver toxicity and stem cell models of hepatotoxicity, from the perspective of the work being done in the MRC Centre for Drug Safety Science, from our role as coordinator of the IMI MIP-DILI project, and will review recent advances in this area made by other groups. The following key themes and questions will be addressed in this talk: The importance of phenotyping developing stem cell models, based on iPS and tissue-derived stem cells, using not only transcriptomic, but also proteomic and functional assays; What does hepatotoxicity look like in an animal model, and can we emulate this in a dish? How should new stem cell-based technologies be used appropriately in hepatotoxicity safety assessment? Can biomarkers help to relate data derived in vivo and in humans back to in vitro models?