The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease

Abstract

The use of pluripotent stem cells (PSCs) has transformed the investigation of liver development and disease. Clinical observations and animal models have provided the foundations of our understanding in these fields. While animal models remain essential research tools, long experimental lead times and low throughput limit the scope of investigations. The ability of PSCs to produce large numbers of human hepatocyte‐like cells, with a given or modified genetic background, allows investigators to use previously incompatible experimental techniques, such as high‐throughput screens, to enhance our understanding of liver development and disease. In this review, we explore how PSCs have expedited our understanding of developmental mechanisms and have been used to identify new therapeutic options for numerous hepatic diseases. We discuss the future directions of the field, including how to further unlock the potential of the PSC model to make it amenable for use with a broader range of assays and a greater repertoire of diseases. Furthermore, we evaluate the current weaknesses of the PSC model and the directions open to researchers to address these limitations. Conclusion: The use of PSCs to model human liver disease and development has and will continue to have substantial impact, which is likely to further expand as protocols used to generate hepatic cells are improved.

HNF4A Regulates the Formation of Hepatic Progenitor Cells from Human iPSC-Derived Endoderm by Facilitating Efficient Recruitment of RNA Pol II

“…For example, the extent of molecular and biochemical analyses that can be performed on these models is limited by the amount of material. Fortunately, the directed differentiation of human pluripotent stem cells has emerged as an alternative model for the study of cell fate [26,27]. Several research groups have demonstrated that cells that share many characteristics with human hepatocytes can be generated from human embryonic (hESCs) and induced pluripotent (hiPSCs) stem cells [28,29,30,31,32,33].…”

Organoid Medicine in Hepatology

“…Several methods were developed to generate organoids from iPSCs, and most protocols attempt to recapitulate the developmental stages of hepatogenesis . The details of hepatic differentiation protocols were reviewed recently . We reported a complex method to generate liver organoids from iPSCs by coculturing with vascular stem cells and mesenchymal stem cells .…”

Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases

“…The possibility to convert hiPSCs into functional hepatocytes allows for novel opportunities in assay development and holds great potential for future pre-clinical and regenerative medicine applications. For example, hiPSC derived from patients suffering from, e.g., inherited metabolic diseases can be used for modeling these types of diseases in vitro [11][12][13]. Combining the hiPSC technology with the constantly progressing genome editing technologies, e.g., CRISPR-Cas9, further increases the potential for disease modeling and therapeutic applications [14,15].…”