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.
Highlights
From all the internal organs that constitute the human body, the liver is the largest one, and its endocrine and exocrine properties make it the largest gland
To trigger hepatoblast proliferation and subsequent hepatocyte differentiation/maturation, hepatocyte growth factor (HGF), Oncostatin M (OSM), and Dexamethasone (DEX) are among the most frequent choices. These differentiation strategies result in the production of what can be called hepatocyte-like cells (HLCs), since current protocols still do not generate hepatocytes with fully mature phenotype when compared to adult hepatocytes
Part of this is due to inadequate screening during preclinical studies and so, the use of human pluripotent stem cells (hPSCs)-derived hepatocytes and liver organoids in this field is of extreme relevance, as hepatotoxicity is the major type of toxicity associated to drug withdrawals (21% of the cases) [124]
Summary
From all the internal organs that constitute the human body, the liver is the largest one, and its endocrine and exocrine properties make it the largest gland. The liver is a central organ in our body that is responsible for homeostasis throughout the human lifespan, performing a complex array of functions [1,2] Such functions include glycogen storage, drug detoxification, control of metabolism, regulation of cholesterol synthesis and transport, urea metabolism, immunological activity, and secretion of plasma proteins like albumin [1]. The generation of hepatocytes derived from human pluripotent stem cells (hPSCs) represents a promising cell source to transform our understanding of liver disease and to change the way it is treated [6] Their remarkable potential can only be translated into practice if the capability to direct the differentiation of hPSCs into the different hepatic lineages can be achieved. The production of the different hepatic cell lineages from hPSCs, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, highlighting their great potential for biomedical applications in regenerative medicine, disease modelling, drug discovery, and hepatotoxicity
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