Stem cell-derived liver cells for drug testing and disease modeling.

Differences between animals and humans in liver pathways now necessitate the use of in vitro models of the human liver for several applications such as drug screening. However, isolated primary human hepatocytes (PHHs) are a limited resource for building such models given shortages of donor organs. In contrast, human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) can be propagated nearly indefinitely and differentiated into hepatocyte-like cells in vitro using soluble factors inspired from liver development. Additionally, iPSCs can be generated from patients with specific genetic backgrounds to study genotype-phenotype relationships. While current protocols to differentiate hESCs and iPSCs into human hepatocyte-like cells (hESC-HHs and iPSC-HHs) still need improvement to yield cells functionally similar to the adult liver, proof-of-concept studies have already shown utility of these cells in drug development and modeling liver diseases such as α1-antitrypsin deficiency, hepatitis B/C viral infections, and malaria. Here, we present an overview of hESC-HH and iPSC-HH culture platforms that have been utilized for the aforementioned applications. We also discuss the use of semiconductor-driven microfabrication tools to precisely control the microenvironment around these cells to enable higher and longer-term liver functions in vitro. Finally, we discuss areas for improvement in creating next generation stem cell-derived liver models. In the future, stem cell-derived hepatocyte-like cells could provide a sustainable cell source for high-throughput drug screening, enabling better mechanistic understanding of human liver diseases for the development of more efficacious and safer therapeutics, and personalized cell-based therapies in the clinic.