Hepatic Endoderm Differentiation from Human Embryonic Stem Cells

MRC-Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
Current Stem Cell Research & Therapy (Impact Factor: 2.21). 03/2010; 5(3):233-44. DOI: 10.2174/157488810791824403
Source: PubMed


Primary human hepatocytes are a scarce resource with variable function which diminishes with time in culture. As a consequence their use in tissue modelling and therapy is restricted. Human embryonic stem cells (hESC) could provide a stable source of human tissue due to their properties of self-renewal and their ability to give rise to all three germ layers. hESCs have the potential to provide an unlimited supply of hepatic endoderm (HE) which could offer efficient tools for drug discovery, disease modelling and therapeutic applications. There has been a major focus on developing protocols to derive functional HE from hESCs. This review focuses on human liver biology and the translation of observations of in vivo systems into developing differentiation protocols to yield hepatic endoderm. It also details the potential role of oxygen tension as a new regulatory mechanism in HE differentiation and points out the importance of the mitochondrial function analysis in defining successful HE generation.

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    • "Induced pluripotent stem (iPS) cells, originally generated from human fibroblasts, are pluripotent and have infinite proliferative potential in vitro [1]. Human iPS (hiPS) cells are expected to have various applications, including for studying hepatic drug metabolism and toxicity [2]. Furthermore, hiPS cell-derived hepatocytes may constitute a source of cells for transplantation in the case of a severe liver disease. "
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    ABSTRACT: In this study, we aimed to elucidate the effects and mechanism of action of valproic acid on hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells. Human induced pluripotent stem cells were differentiated into endodermal cells in the presence of activin A and then into hepatic progenitor cells using dimethyl sulfoxide. Hepatic progenitor cells were matured in the presence of hepatocyte growth factor, oncostatin M, and dexamethasone with valproic acid that was added during the maturation process. After 25 days of differentiation, cells expressed hepatic marker genes and drug-metabolizing enzymes and exhibited drug-metabolizing enzyme activities. These expression levels and activities were increased by treatment with valproic acid, the timing and duration of which were important parameters to promote differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells into hepatocytes. Valproic acid inhibited histone deacetylase activity during differentiation of human induced pluripotent stem cells, and other histone deacetylase inhibitors also enhanced differentiation into hepatocytes. In conclusion, histone deacetylase inhibitors such as valproic acid can be used to promote hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Such studies will undoubtedly lead to an improved understanding of human development and cell physiology. Additionally, the development of high-fidelity cell-based resources from renewable sources, such as stem cells, has a significant role to play in many aspects of modern medicine (Hannoun et al., 2010b). "
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    ABSTRACT: The coordination of signalling pathways within the cell is vital for normal human development and post-natal tissue homeostasis. Gene expression and function is therefore tightly controlled at a number of levels. We investigated the role that post-translational modifications play during human hepatocyte differentiation. In particular, we examined the role of the small ubiquitin-like modifier (SUMO) proteins in this process. We used a human embryonic stem cell (hESC)-based model of hepatocyte differentiation to follow changes in protein SUMOylation. Moreover, to confirm the results derived from our cell-based system, we performed in vitro conjugation assays to characterise SUMO modification of a key liver-enriched transcription factor, HNF4α. Our analyses indicate that SUMOylation plays an important role during hepatocellular differentiation and this is mediated, in part, through regulation of the stability of HNF4α in a ubiquitin-dependent manner. Our study provides a better understanding of SUMOylation during human hepatocyte differentiation and maturation. Moreover, we believe the results will stimulate interest in the differentiation and phenotypic regulation of other somatic cell types.
    Full-text · Article · Apr 2012 · Journal of Cell Science
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    • "Multiple O2-sensitive intracellular mechanisms such as hypoxia-inducible transcription factors (HIFs), the environmental sensing of mammalian target of rapamycin (mTOR) and the endoplasmic reticulum (ER) stress response have been described [102]. It appears that hypoxia increases the mitochondrial membrane potential and subsequently reactive oxygen species which activate HIF-1 expression [105]. "
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    ABSTRACT: Orthotropic liver transplantation is the only established treatment for end-stage liver diseases. Utilization of hepatocyte transplantation and bio-artificial liver devices as alternative therapeutic approaches requires an unlimited source of hepatocytes. Stem cells, especially embryonic stem cells, possessing the ability to produce functional hepatocytes for clinical applications and drug development, may provide the answer to this problem. New discoveries in the mechanisms of liver development and the emergence of induced pluripotent stem cells in 2006 have provided novel insights into hepatocyte differentiation and the use of stem cells for therapeutic applications. This review is aimed towards providing scientists and physicians with the latest advancements in this rapidly progressing field.
    Full-text · Article · Feb 2011 · Stem cell reviews
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