Emerging trends in modeling human liver disease in vitro

Abstract

The liver executes 500+ functions, such as protein synthesis, xenobiotic metabolism, bile production, and metabolism of carbohydrates/fats/proteins. Such functions can be severely degraded by drug-induced liver injury, nonalcoholic fatty liver disease, hepatitis B and viral infections, and hepatocellular carcinoma. These liver diseases, which represent a significant global health burden, are the subject of novel drug discovery by the pharmaceutical industry via the use of in vitro models of the human liver, given significant species-specific differences in disease profiles and drug outcomes. Isolated primary human hepatocytes (PHHs) are a physiologically relevant cell source to construct such models; however, these cells display a rapid decline in the phenotypic function within conventional 2-dimensional monocultures. To address such a limitation, several engineered platforms have been developed such as high-throughput cellular microarrays, micropatterned cocultures, self-assembled spheroids, bioprinted tissues, and perfusion devices; many of these platforms are being used to coculture PHHs with liver nonparenchymal cells to model complex cell cross talk in liver pathophysiology. In this perspective, we focus on the utility of representative platforms for mimicking key features of liver dysfunction in the context of chronic liver diseases and liver cancer. We further discuss pending issues that will need to be addressed in this field moving forward. Collectively, these in vitro liver disease models are being increasingly applied toward the development of new therapeutics that display an optimal balance of safety and efficacy, with a focus on expediting development, reducing high costs, and preventing harm to patients.