Human PSC-derived liver cells and their applications for disease models and drug discovery

The liver comprises hepatic parenchymal cells, primarily hepatocytes, and non-parenchymal cells such as liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and cholangiocytes. These cell types interact with each other to maintain homeostasis through metabolism, detoxification, and protein synthesis. Such cellular interactions also play crucial roles in regulating the onset and progression of liver diseases. Consequently, the development of in vitro multicellular liver models is vital for elucidating the mechanisms underlying liver diseases and for evaluating the efficacy and toxicity of novel therapeutic drugs. Given their ability to proliferate and differentiate into diverse cell types in vitro, human pluripotent stem cells (hPSCs), including embryonic stem cells and induced PSCs, offer valuable potential for generating various liver cell types and constructing liver disease models for drug discovery research. Furthermore, patient-derived or gene-edited iPSCs can be employed to model genetic liver disorders. This review summarizes the development of differentiation protocols for hPSC-derived hepatocytes, LSECs, HSCs, and cholangiocytes, as well as their applications in drug discovery research.