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    Novel developmental biology-based protocol of embryonic stem cell differentiation to morphologically sound and functional yet immature hepatocytes

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    Authors
    Bukong, Terence N.
    Lo, Tracie
    Szabo, Gyongyi
    Dolganiuc, Angela
    UMass Chan Affiliations
    Department of Medicine, Division of Gastroenterology
    Document Type
    Journal Article
    Publication Date
    2012-05-02
    Keywords
    Activins
    Bone Morphogenetic Protein 2
    Cell Differentiation
    Cell Proliferation
    Cell Survival
    Cells, Cultured
    Drug Combinations
    Embryonic Stem Cells
    Fibroblast Growth Factors
    Flow Cytometry
    Hepatocytes
    Humans
    Polymerase Chain Reaction
    Research Design
    Transcription Factors
    Up-Regulation
    Cell and Developmental Biology
    Cells
    Digestive System Diseases
    Gastroenterology
    Hepatology
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    Link to Full Text
    http://dx.doi.org/10.1111/j.1478-3231.2011.02743.x
    Abstract
    BACKGROUND/AIMS: Liver diseases are common in the United States and often require liver transplantation; however, donated organs are limited and thus alternative sources for liver cells are in high demand. Embryonic stem cells (ESC) can provide a continuous and readily available source of liver cells. ESC differentiation to liver cells is yet to be fully understood and comprehensive differentiation protocols are yet to be defined. Here, we aimed to achieve human (h)ESC differentiation into mature hepatocytes using defined recombinant differentiation factors and metabolites. METHODS: Embryonic stem cell H1 line was sub-cultured on feeder layer. We induced hESCs into endodermal differentiation succeeded by early/late hepatic specification and finally into hepatocyte maturation using step combinations of Activin A and fibroblast growth factor (FGF)-2 for 7 days; followed by FGF-4 and bone morphogenic protein 2 (BMP2) for 7 days, succeeded by FGF-10 + hepatocyte growth factor 4 + epidermal growth factor for 14 days. Specific inhibitors/stimulators were added sequentially throughout differentiation. Cells were analysed by PCR, flow cytometry, microscopy or functional assays. RESULTS: Our hESC differentiation protocol resulted in viable cells with hepatocyte shape and morphology. We observed gradual changes in cell transcriptome, including up-regulation of differentiation-promoting GATA4, GATA6, POU5F1 and HNF4 transcription factors, steady levels of stemness-promoting SOX-2 and low levels of Nanog, as defined by PCR. The hESC-derived hepatocytes expressed alpha-antitrypsin, CD81, cytokeratin 8 and low density lipoprotein (LDL) receptor. The levels of alpha-fetoprotein and proliferation marker Ki-67 in hESC-derived hepatocytes remained elevated. Unlike stem cells, the hESC-derived hepatocytes performed LDL uptake, produced albumin and alanine aminotransferase and had functional alcohol dehydrogenase. CONCLUSION: We report a novel protocol for hESC differentiation into morphological and functional yet immature hepatocytes as an alternative method for hepatocyte generation.
    Source

    Liver Int. 2012 May;32(5):732-41. doi: 10.1111/j.1478-3231.2011.02743.x. Link to article on publisher's site

    DOI
    10.1111/j.1478-3231.2011.02743.x
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31057
    PubMed ID
    22292891
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1111/j.1478-3231.2011.02743.x
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