The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
Small-Molecule-Driven Hepatocyte Differentiation of Human Pluripotent Stem Cells
Open accessAbstract
The differentiation of pluripotent stem cells to hepatocytes is well established, yet current methods suffer from several drawbacks. These include a lack of definition and reproducibility, which in part stems from continued reliance on recombinant growth factors. This has remained a stumbling block for the translation of the technology into industry and the clinic for reasons associated with cost and quality. We have devised a growth-factor-free protocol that relies on small molecules to differentiate human pluripotent stem cells toward a hepatic phenotype. The procedure can efficiently direct both human embryonic stem cells and induced pluripotent stem cells to hepatocyte-like cells. The final population of cells demonstrates marker expression at the transcriptional and protein levels, as well as key hepatic functions such as serum protein production, glycogen storage, and cytochrome P450 activity.
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“While growth factors could be costly and unstable, and many small-molecule drugs can affect multiple pathways resulting in poor reproducibility78”
From Organoids (2022) · cites this paper as [78]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“The differentiation protocol utilized was developed and optimized from the published literatures18–21, specifically chosen for its capacity to generate iHLOs with high CYP enzyme activity, particularly CYP3A4, which is crucial for drug metabolism and toxicology evaluations.”
From Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology (2026) · cites this paper as [18]
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“This protocol was chosen due to its demonstrated capacity to generate iHLOs with high CYP enzyme activity, particularly CYP3A4, which is crucial for our subsequent compound or drug metabolism and toxicology evaluations.”
From Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology (2026) · cites this paper as [18]
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Sato, N., Meijer, L., Skaltsounis, A., Greengard, P., & Brivanlou, A. H. (2003) · Nature Medicine · doi:10.1038/nm979 · Cited by 2,139 · cited 2×
“…well documented that BIO and CHIR99021 are potent pharmacological GSK3-specific inhibitors that result in activation of the Wnt signaling pathway (Sato et al., 2004; Sineva and Pospelov, 2010), so we next assessed the ability of the protein Wnt3a alone to drive differentiation toward DE. Figure…”
BackgroundEfficient differentiation of human embryonic stem cells to definitive endoderm
D'Amour, K. A., Agulnick, A. D., Eliazer, S., Kelly, O. G., Kroon, E., & Baetge, E. E. (2005) · Nature Biotechnology · doi:10.1038/nbt1163 · Cited by 1,730
Lian, X., Hsiao, C., Wilson, G., Zhu, K., Hazeltine, L. B., Azarin, S. M., Raval, K. K., Zhang, J., Kamp, T. J., & Palecek, S. P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200250109 · Cited by 1,717
Itskovitz‐Eldor, J., Schuldiner, M., Kenyagin‐Karsenti, D., Eden, A., Yanuka, O., Amit, M., Soreq, H., & Benvenisty, N. (2000) · Molecular Medicine · doi:10.1007/bf03401776 · Cited by 1,502
Embryonic stem cell trials for macular degeneration: a preliminary report
Schwartz, S. D., Hubschman, J.-P., Heilwell, G., Franco-Cardenas, V., Pan, C. K., Ostrick, R. M., Mickunas, E., Gay, R., Klimanskaya, I., & Lanza, R. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60028-2 · Cited by 1,409 · cited 1×
“Meanwhile, cell culture and production technologies are rapidly improving, and the first instances of pluripotent-cellderived therapies have entered clinical trials (Schwartz et al., 2012).”
BackgroundHighly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells
Si-Tayeb, K., Noto, F. K., Nagaoka, M., Li, J., Battle, M. A., Duris, C., North, P. E., Dalton, S., & Duncan, S. A. (2010) · Hepatology · doi:10.1002/hep.23354 · Cited by 1,282 · cited 2×
“…growth factor (VEGF), epidermal growth factor (EGF), and bone morphogenetic protein 4 (BMP4) (Agarwal et al., 2008; Brolén et al., 2010; Cai et al., 2007; Chen et al., 2012; Hay et al., 2008; Liu et al., 2010; Si-Tayeb et al., 2010b; Song et al., 2009; Sullivan et al., 2010; Touboul et al., 2010).”
BackgroundMethodOrganogenesis and development of the liver
Si-Tayeb, K., Lemaigre, F. P., & Duncan, S. A. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.01.011 · Cited by 800 · cited 2×
“…growth factor (VEGF), epidermal growth factor (EGF), and bone morphogenetic protein 4 (BMP4) (Agarwal et al., 2008; Brolén et al., 2010; Cai et al., 2007; Chen et al., 2012; Hay et al., 2008; Liu et al., 2010; Si-Tayeb et al., 2010b; Song et al., 2009; Sullivan et al., 2010; Touboul et al., 2010).”
BackgroundMethodDepletion of definitive gut endoderm in Sox17 -null mutant mice
Kanai-Azuma, M., Kanai, Y., Gad, J. M., Tajima, Y., Taya, C., Kurohmaru, M., Sanai, Y., Yonekawa, H., Yazaki, K., Tam, P. P. L., et al. (2002) · Development · doi:10.1242/dev.129.10.2367 · Cited by 704
Sasaki, H., & Hogan, B. L. M. (1993) · Development · doi:10.1242/dev.118.1.47 · Cited by 665
Directed differentiation of human embryonic stem cells into functional hepatic cells†
Cai, J., Zhao, Y., Liu, Y., Ye, F., Song, Z., Qin, H., Meng, S., Chen, Y., Zhou, R., Song, X., et al. (2007) · Hepatology · doi:10.1002/hep.21582 · Cited by 628 · cited 3×
“…endothelial growth factor (VEGF), epidermal growth factor (EGF), and bone morphogenetic protein 4 (BMP4) (Agarwal et al., 2008; Brolén et al., 2010; Cai et al., 2007; Chen et al., 2012; Hay et al., 2008; Liu et al., 2010; Si-Tayeb et al., 2010b; Song et al., 2009; Sullivan et al., 2010; Touboul…”
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Items 201–211 of 211
Gandhi, N. N., & Rajagopalan, P. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.09.681454
“A common approach is the addition of chemical cocktails, including different growth factors and their agonists or chemical molecules (12, 13, 15, 16).”
InfluentialPan, T., Wang, N., Zhang, J., Yang, F., Chen, Y., Zhuang, Y., Xu, Y., Fang, J., You, K., Lin, X., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19582308
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947816
Pan, T., Tao, J., Chen, Y., Zhang, J., Getachew, A., Zhuang, Y., Wang, N., Xu, Y., Tan, S., Fang, J., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14121675
Fourrier, A. (2019) · theses.fr (ABES) · doi:10.70675/47d480a4z453ez42abzbdb6z8a3aae86f375
Zhou, Q., Zhong, Z., Sun, X., Xie, X., Liu, T., Zhou, X., & Sun, P. (2026) · Stem Cells and Development · doi:10.1177/15473287261436294
“32 Furthermore, the mTORC1 and BMP signaling pathways are also critical regulators of cell growth and fate speci fi cation.”
Sainger, S., Chikara, A., Kumari, M., Kumari, D., Jaipal, P., Ranjan, S., Gujjar, S., Kumar, Y., Kumar, A. T. R., & Mathapati, S. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.02.729501
Minocha, E., Gupta, A., Schmidt, N., Rm, G., Purdy, J. G., & Wertheim, J. A. (2026) · Advanced Science · doi:10.1002/advs.202521373
“Quantitative PCR analysis also showed significant upregulation of mature hepatic markers: ALB , SER-PINA1 , HNF4A , and CYP3A4 [ 20 ] as well as markers specific for cholangiocytes, endothelial cells, stellate cells, and Kupffer cells by day 21 of differentiation (Figure 2H ).”
Roman, G., Lauritzen, K. H., Smolkova, B., Almaas, R., Sandset, P. M., Stavik, B., Sullivan, G. J., & Chollet, M. E. (2026) · Stem Cell Reviews and Reports · doi:10.1007/s12015-026-11221-6
Self-citationLiao, Y., Yang, J., Kuo, H., Chen, Y., Lin, Y., Sachdev, S., Kim, D., Roberts, R. M., Yuan, Y., & Ezashi, T. (2026) · FEBS Journal · doi:10.1111/febs.70733
Metadata
- Authors
- Siller, R., Greenhough, S., Naumovska, E., & Sullivan, G. J.
- Affiliations
- University of Oslo (NO)
- Oslo University Hospital (NO)
- Corresponding author
- Sullivan, Gareth J.
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 4
- Issue
- 5
- Pages
- 939-952
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC4437467
- OpenAlex
- W2012281335
- Cited by
- 203
- References
- 48
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 11 · 2023: 13 · 2022: 19 · 2021: 30 · 2020: 25 · 2019: 15 · 2018: 27 · 2017: 19 · 2016: 19 · 2015: 6
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- hepatocyte differentiation, human pluripotent stem cells, small molecules, human embryonic stem cells, induced pluripotent stem cells, hepatocyte-like cells, glycogen storage, cytochrome P450 activity, hepatic differentiation
- MeSH terms
- Blood Proteins, Cell Differentiation, Cells, Cultured, Dexamethasone, Dimethyl Sulfoxide, Glycogen, Humans, Microscopy, Fluorescence, Oligopeptides, Proto-Oncogene Proteins c-met, Hepatocytes, Glycogen Synthase Kinase 3, Pluripotent Stem Cells, Small Molecule Libraries
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