Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo
Abstract
The potential to differentiate human embryonic stem cells (hESCs) in vitro to provide an unlimited source of human hepatocytes for use in biomedical research, drug discovery, and the treatment of liver diseases holds great promise. Here we describe a three-stage process for the efficient and reproducible differentiation of hESCs to hepatocytes by priming hESCs towards definitive endoderm with activin A and sodium butyrate prior to further differentiation to hepatocytes with dimethyl sulfoxide, followed by maturation with hepatocyte growth factor and oncostatin M. We have demonstrated that differentiation of hESCs in this process recapitulates liver development in vivo: following initial differentiation, hESCs transiently express characteristic markers of the primitive streak mesendoderm before turning to the markers of the definitive endoderm; with further differentiation, expression of hepatocyte progenitor cell markers and mature hepatocyte markers emerged sequentially. Furthermore, we have provided evidence that the hESC-derived hepatocytes are able to carry out a range of hepatocyte functions: storage of glycogen, and generation and secretion of plasma proteins. More importantly, the hESC-derived hepatocytes express several members of cytochrome P450 isozymes, and these P450 isozymes are capable of converting the substrates to metabolites and respond to the chemical stimulation. Our results have provided evidence that hESCs can be differentiated efficiently in vitro to fu…
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HNF4A+ liver progenitors were typically formed on later days (by day 10-14) in other differentiation protocols.
“whereas HNF4A+ liver progenitors were typically formed on later days (by day 10–14) in other differentiation protocols (Carpentier et al., 2016; Hay et al., 2008; Si-Tayeb et al., 2010; Zhao et al., 2013).”
From A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells (2018) · cites this paper as Hay et al., 2008
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Panduro, A., Shalaby, F., & Shafritz, D. A. (1987) · Genes & Development · doi:10.1101/gad.1.10.1172 · Cited by 96 · see citing works
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A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells
Ang, L. T., Tan, A. K. Y., Autio, M. I., Goh, S. H., Choo, S. H., Lee, K. L., Tan, J., Pan, B., Lee, J. J. H., Lum, J. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.087 · Cited by 220 · see citing works
“35% HNF4A+ pure liver bud progenitors were produced (Figure S3A), whereas HNF4A + liver progenitors were typically formed on later days (by day 10–14) in other differentiation protocols (Carpentier et al., 2016; Hay et al., 2008; Si-Tayeb et al., 2010; Zhao et al., 2013).”
BackgroundCell therapy for advanced liver diseases: repair or rebuild
Dwyer, B. J., Macmillan, M. T., Brennan, P. N., & Forbes, S. J. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2020.09.014 · Cited by 141 · see citing works
Large‐Scale Production of LGR5‐Positive Bipotential Human Liver Stem Cells
Schneeberger, K., Sánchez‐Romero, N., Ye, S., van Steenbeek, F. G., Oosterhoff, L. A., Pla Palacin, I., Chen, C., van Wolferen, M. E., van Tienderen, G., Lieshout, R., et al. (2020) · Hepatology · doi:10.1002/hep.31037 · Cited by 141 · see citing works
Liver tissue engineering and cell sources: issues and challenges
Palakkan, A. A., Hay, D. C., PR, A. K., TV, K., & Ross, J. A. (2013) · Liver International · doi:10.1111/liv.12134 · Cited by 130 · see citing works
Self-citationWong, J. C. Y., Gao, S. Y., Lees, J. G., Best, M. B., Wang, R., & Tuch, B. E. (2010) · Cell Adhesion & Migration · doi:10.4161/cam.4.1.10627 · Cited by 37 · see citing works
Ethnically diverse pluripotent stem cells for drug development
Fakunle, E. S., & Loring, J. F. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.10.007 · Cited by 27 · see citing works
Yang, G., Si-Tayeb, K., Corbineau, S., Vernet, R., Gayon, R., Dianat, N., Martinet, C., Clay, D., Goulinet-Mainot, S., Tachdjian, G., et al. (2013) · BMC Biology · doi:10.1186/1741-7007-11-86 · Cited by 26 · see citing works
Advancements in MAFLD Modeling with Human Cell and Organoid Models
Wang, S.-X., Yan, J.-S., & Chan, Y.-S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911850 · Cited by 22 · see citing works
- Authors
- Hay, D. C., Zhao, D., Fletcher, J., Hewitt, Z. A., McLean, D., Urruticoechea-Uriguen, A., Black, J. R., Elcombe, C., Ross, J. A., Wolf, R., & Cui, W.
- Affiliations
- Roslin Institute (GB)
- CXR Biosciences Ltd. James Lindsay Place, Dundee, United Kingdom
- Imperial College London (GB)
- University of Edinburgh (GB)
- Corresponding author
- Cui, Wei
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-01-31
- Volume
- 26
- Issue
- 4
- Pages
- 894-902
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W2053355345
- Cited by
- 441
- References
- 1
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 9 · 2023: 14 · 2022: 16 · 2021: 25 · 2020: 27 · 2019: 22 · 2018: 30 · 2017: 24 · 2016: 33 · 2015: 34 · 2014: 35 · 2013: 30 · 2012: 30
- FWCI
- 13.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- University of Sheffield
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- human embryonic stem cells, hepatocyte differentiation, definitive endoderm, liver development, hepatocyte growth factor, oncostatin M, dimethyl sulfoxide, activin A, sodium butyrate, cytochrome P450 isozymes, glycogen storage, plasma protein secretion, hepatocyte function, drug toxicity testing
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Humans, Liver, Biomarkers, Cell Culture Techniques, Hepatocytes, Organogenesis, Mice, Embryonic Stem Cells
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