Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

Abstract

Liver disease is one of the leading causes of death worldwide, leading to the death of approximately 2 million people per year. Current therapies include orthotopic liver transplantation, however, donor organ shortage remains a great challenge. In addition, the development of novel therapeutics has been limited due to the lack of in vitro models that mimic in vivo liver physiology. Accordingly, hepatic cell lineages derived from human pluripotent stem cells (hPSCs) represent a promising cell source for liver cell therapy, disease modelling, and drug discovery. Moreover, the development of new culture systems bringing together the multiple liver-specific hepatic cell types triggered the development of hPSC-derived liver organoids. Therefore, these human liver-based platforms hold great potential for clinical applications. In this review, the production of the different hepatic cell lineages from hPSCs, including hepatocytes, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, while current biomedical applications will be highlighted.

Keywords: disease modeling; drug screening; hepatic cell lineages; hepatocyte differentiation; human pluripotent stem cells; liver organoids; non-parenchymal liver cells.

Figure 1

Current strategies for the generation of human pluripotent stem cell (hPSC)-derived liver organoids. So far, liver organoids have been generated by (A–C) co-culture of different cell types, including hPSCs, differentiated hepatic cell lineages, or isolated human cells with potential to promote liver organoid differentiation/maturation; (D–F) homogeneous cell populations that, through differentiation, are capable of generating cellular constructs with structural and physiological complexity. STM, septum transversum mesenchymal cells; HSCs, hepatic stellate cells.

Figure 2

Clinical applications for hPSC-derived hepatic cells and liver organoids. Isolated somatic cells from patients can be cultured and reprogrammed into patient-specific hiPSCs. These cells represent a promising cell source for cell therapy, as differentiated hepatocytes can be used for transplantation in regenerative medicine strategies. Additionally, differentiated hepatic cell lineages or generated liver organoids can be applied in disease modelling, as well as drug development and hepatotoxicity assays.