Generation of Functional Human Hepatic Endoderm From Human Induced Pluripotent Stem Cells
Open accessAbstract
With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled with direct differentiation to a defined lineage, such as hepatic endoderm (HE), iPSCs would revolutionize the way we study human liver biology and generate efficient “off the shelf” models of human liver disease. Here, we show the “proof of concept” that iPSC lines representing both male and female sexes and two ethnic origins can be differentiated to HE at efficiencies of between 70%–90%, using a method mimicking physiological relevant condition. The iPSC-derived HE exhibited hepatic morphology and expressed the hepatic markers albumin and E-cadherin, as assessed by immunohistochemistry. They also expressed alpha-fetoprotein, hepatocyte nuclear factor-4a, and a metabolic marker, cytochrome P450 7A1 (Cyp7A1), demonstrating a definitive endodermal lineage differentiation. Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin, and alpha-fetoprotein, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and CYP3A4 metabolism, which is essential for drug and toxicology testing. Conclusion: This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSCs that exhibits key attributes of hepatocytes, and the potential application of iPSC-derived HE in studying human liver biology. In particular, iPSCs from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionize predictive drug toxicology assays and allow the creation of in vitro hepatic disease models. (Hepatology 2009.)
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The differentiation protocol used was developed and optimized from published literature and chosen for its capacity to generate iHLOs with high CYP enzyme activity, particularly CYP3A4.
“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 [19]
The Experimental Procedures describe a differentiation protocol adapted from published work, and the Results report CYP3A4 activity in the resulting iPSC-derived hepatic endoderm. The paper does not describe generating iHLOs or establish that their CYP enzyme activity is high; its activity measurements concern hepatic endoderm cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe protocol was chosen due to its demonstrated capacity to generate iHLOs with high CYP enzyme activity, particularly CYP3A4.
“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 [19]
The Results report CYP1A2 and CYP3A4 activity in all three iPSC-derived hepatic endoderm lines, supporting the protocol’s relevance to drug-metabolism testing. The Cell Culture and Differentiation section describes hepatocyte-like cells, not iHLOs, and the Results do not establish that their CYP enzyme activity was high. The reported ~6000-fold increase in CYP3A4 concerns expression relative to undifferentiated iPS cells, not measured enzyme activity. (LLM, conf=0.88)
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Cites
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007) · Cell · doi:10.1016/j.cell.2007.11.019 · Cited by 20,221 · see citing works
Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells
Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., et al. (2007) · Science · doi:10.1126/science.1151526 · Cited by 10,310 · see citing works
Reprogramming of human somatic cells to pluripotency with defined factors
Park, I.-H., Zhao, R., West, J. A., Yabuuchi, A., Huo, H.-G., Ince, T., Lerou, P., Lensch, M., & Daley, G. Q. (2008) · Nature · doi:10.1038/nature06534 · Cited by 3,028 · see citing works
Self-citationHuman induced pluripotent stem cells free of vector and transgene sequences
Yu, J., Hu, K., Smuga-Otto, K., Tian, S., Stewart, R., Slukvin, I. I., & Thomson, J. A. (2009) · Science · doi:10.1126/science.1172482 · Cited by 2,386 · see citing works
Disease-Specific Induced Pluripotent Stem Cells.
Park, I.-H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M. W., Cowan, C., Hochedlinger, K., & Daley, G. Q. (2008) · Cell · doi:10.1016/j.cell.2008.07.041 · Cited by 2,196 · cited 3× · see citing works
“iPS cells from diabetic North American Indian (JDM-iPS1) and female Caucasian (PGP9iPS1) were reported previously [6–7].”
BackgroundMethodInfluentialSelf-citationKleinman, H. K., McGarvey, M. L., Liotta, L. A., Robey, P. G., Tryggvason, K., & Martin, G. R. (1982) · Biochemistry · doi:10.1021/bi00267a025 · Cited by 1,231 · see citing works
Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells
Ball, M. P., Li, J. B., Gao, Y., Lee, J., LeProust, E. M., Park, I., Xie, B., Daley, G. Q., & Church, G. M. (2009) · Nature Biotechnology · doi:10.1038/nbt.1533 · Cited by 1,087 · see citing works
Self-citationInduction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells
Yasunaga, M., Tada, S., Torikai-Nishikawa, S., Nakano, Y., Okada, M., Jakt, L. M., Nishikawa, S., Chiba, T., Era, T., & Nishikawa, S.-I. (2005) · Nature Biotechnology · doi:10.1038/nbt1167 · Cited by 471 · see citing works
Hay, D. C., Fletcher, J. M., Payne, C. M., Terrace, J. D., Gallagher, R., Snoeys, J., Black, J. R., Wojtacha, D., Samuel, K., Hannoun, Z., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806522105 · Cited by 434 · see citing works
Self-citationProkhorova, T. A., Harkness, L., Frandsen, U., Ditzel, N., Schrøder, H. D., Burns, J. S., & Kassem, M. S. (2008) · Stem Cells and Development · doi:10.1089/scd.2007.0266 · Cited by 278 · see citing works
Asahina, K., Fujimori, H., Shimizu‐Saito, K., Kumashiro, Y., Okamura, K., Tanaka, Y., Teramoto, K., Arii, S., & Teraoka, H. (2004) · Genes to Cells · doi:10.1111/j.1365-2443.2004.00809.x · Cited by 103 · see citing works
Progress and future challenges in stem cell-derived liver technologies
Dalgetty, D., Medine, C. N., Iredale, J. P., & Hay, D. C. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00138.2009 · Cited by 88 · see citing works
Self-citationGadue, P. J., Gouon–Evans, V., Cheng, X., Wandzioch, E., Zaret, K. S., Grompe, M., Streeter, P. R., & Keller, G. M. (2009) · Stem Cells · doi:10.1002/stem.147 · Cited by 40 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors
Huang, P., He, Z., Ji, S., Sun, H., Xiang, D., Liu, C., Hu, Y., Wang, X., & Hui, L. (2011) · Nature · doi:10.1038/nature10116 · Cited by 864 · see citing works
Induced pluripotent stem cells — opportunities for disease modelling and drug discovery
Grs̆ković, M., Javaherian, A., Strulovici, B., & Daley, G. Q. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3577 · Cited by 474 · see citing works
Self-citationThe therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles
Katsuda, T., Kosaka, N., Takeshita, F., & Ochiya, T. (2013) · PROTEOMICS · doi:10.1002/pmic.201200373 · Cited by 425 · see citing works
Singh, V. K., Kalsan, M., Kumar, N., Saini, A., & Chandra, R. (2015) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2015.00002 · Cited by 421 · see citing works
Technical Challenges in Using Human Induced Pluripotent Stem Cells to Model Disease
Saha, K., & Jaenisch, R. (2009) · Cell Stem Cell · doi:10.1016/j.stem.2009.11.009 · Cited by 411 · see citing works
Organotypic liver culture models: meeting current challenges in toxicity testing
LeCluyse, E. L., Witek, R. P., Andersen, M. E., & Powers, M. J. (2012) · Critical Reviews in Toxicology · doi:10.3109/10408444.2012.682115 · Cited by 363 · see citing works
Baxter, M. A., Withey, S., Harrison, S. P., Segeritz, C., Zhang, F., Atkinson-Dell, R., Rowe, C., Gerrard, D. T., Sison-Young, R. L. C., Jenkins, R., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.10.016 · Cited by 353 · see citing works
Cell therapy for liver disease: From liver transplantation to cell factory
Forbes, S. J., Gupta, S. K., & Dhawan, A. K. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.02.040 · Cited by 327 · see citing works
Self-citationDonor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells
Kajiwara, M., Aoi, T., Okita, K., Takahashi, R., Inoue, H., Takayama, N., Endô, H., Eto, K., Toguchida, J., Üemoto, S., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209979109 · Cited by 321 · see citing works
Cell and tissue engineering for liver disease
Bhatia, S. N., Underhill, G. H., Zaret, K. S., & Fox, I. J. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3005975 · Cited by 309 · see citing works
Chen, Y.-F., Tseng, C.-Y., Wang, H.-W., Kuo, H.-C., Yang, V. W., & Lee, O. K. (2012) · Hepatology · doi:10.1002/hep.24790 · Cited by 291 · see citing works
Prokhorova, T. A., Harkness, L., Frandsen, U., Ditzel, N., Schrøder, H. D., Burns, J. S., & Kassem, M. S. (2008) · Stem Cells and Development · doi:10.1089/scd.2007.0266 · Cited by 278 · see citing works
Generation of hepatobiliary organoids from human induced pluripotent stem cells
Wu, F., Wu, D., Ren, Y., Huang, Y., Feng, B., Zhao, N. J., Zhang, T., Chen, X., Chen, S., & Xu, A. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.12.028 · Cited by 264 · see citing works
Identification of small molecules for human hepatocyte expansion and iPS differentiation
Shan, J., Schwartz, R. E., Ross, N. T., Logan, D. J., Thomas, D., Duncan, S. A., North, T. E., Goessling, W., Carpenter, A. E., & Bhatia, S. N. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1270 · Cited by 254 · see citing works
Generation of Endoderm-Derived Human Induced Pluripotent Stem Cells From Primary Hepatocytes
Liu, H., Ye, Z., Kim, Y., Sharkis, S. J., & Jang, Y.-Y. (2010) · Hepatology · doi:10.1002/hep.23626 · Cited by 247 · see citing works
In Vivo Liver Regeneration Potential of Human Induced Pluripotent Stem Cells from Diverse Origins
Liu, H., Kim, Y., Sharkis, S. J., Marchionni, L., & Jang, Y.-Y. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002376 · Cited by 248 · see citing works
Assessing the Safety of Stem Cell Therapeutics
Goldring, C. E. P., Duffy, P. A., Benvenisty, N., Andrews, P. W., Ben-David, U., Eakins, R., French, N., Hanley, N. A., Kelly, L., Kitteringham, N. R., et al. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.05.012 · Cited by 245 · see citing works
Induced Pluripotent Stem Cells as a Disease Modeling and Drug Screening Platform
Ebert, A., Liang, P., & Wu, J. C. (2012) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e318247f642 · Cited by 223 · see citing works
The Use of Induced Pluripotent Stem Cells in Drug Development
Inoue, H., & Yamanaka, S. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.38 · Cited by 222 · see citing works
A public resource facilitating clinical use of genomes
Ball, M. P., Thakuria, J. V., Zaranek, A. W., Clegg, T., Rosenbaum, A. M., Wu, X., Angrist, M. H., Bhak, J., Bobe, J. R., Callow, M. J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1201904109 · Cited by 222 · see citing works
Self-citationSmall-Molecule-Driven Hepatocyte Differentiation of Human Pluripotent Stem Cells
Siller, R., Greenhough, S., Naumovska, E., & Sullivan, G. J. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.04.001 · Cited by 203 · see citing works
“We finally settled on a modified formulation of Leibovitz L-15 medium (L-15), which has been described in the literature as a standard method to generate mature hepatocytes (Hay et al., 2008; Sullivan et al., 2010).”
BackgroundMethodInfluentialSelf-citationZhang, S., Chen, S., Li, W., Guo, X., Zhao, P., Xu, J., Chen, Y., Pan, Q., Liu, X., Zychlinski, D., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr223 · Cited by 173 · see citing works
Wu, X., Robotham, J. M., Lee, E., Dalton, S., Kneteman, N. M., Gilbert, D. M., & Tang, H. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002617 · Cited by 166 · see citing works
Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells
Kim, Y., Kang, K., Lee, S. B., Seo, D., Yoon, S., Kim, S. J., Jang, K., Jung, Y. K., Lee, K. G., Factor, V. M., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.09.007 · Cited by 167 · see citing works
A Chemically Defined Hydrogel for Human Liver Organoid Culture
Ye, S., Boeter, J. W. B., Mihajlovic, M., van Steenbeek, F. G., van Wolferen, M. E., Oosterhoff, L. A., Marsee, A., Caiazzo, M., van der Laan, L. J. W., Penning, L. C., et al. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202000893 · Cited by 165 · see citing works
Ogawa, S., Surapisitchat, J., Virtanen, C., Ogawa, M., Niapour, M., Sugamori, K. S., Wang, S., Tamblyn, L., Guillemette, C., Hoffmann, E., et al. (2013) · Development · doi:10.1242/dev.090266 · Cited by 161 · see citing works
Constructing and Deconstructing Stem Cell Models of Neurological Disease
Han, S. S. W., Williams, L. A., & Eggan, K. C. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.003 · Cited by 159 · see citing works
Present state and future perspectives of using pluripotent stem cells in toxicology research
Wobus, A. M., & Löser, P. (2011) · Archives of Toxicology · doi:10.1007/s00204-010-0641-6 · Cited by 161 · see citing works
Ghodsizadeh, A., Taei, A., Totonchi, M., Seifinejad, A., Gourabi, H., Pournasr, B., Aghdami, N., Malekzadeh, R., Almadani, N., Salekdeh, G. H., et al. (2010) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9189-3 · Cited by 154 · see citing works
Induced Pluripotent Stem Cells for Regenerative Medicine
Hirschi, K. K., Li, S., & Roy, K. (2014) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071813-105108 · Cited by 149 · see citing works
Recombinant Laminins Drive the Differentiation and Self-Organization of hESC-Derived Hepatocytes
Cameron, K., Tan, R., Schmidt‐Heck, W., Campos, G., Lyall, M. J., Wang, Y., Lucendo‐Villarin, B., Szkolnicka, D., Bates, N., Kimber, S. J., et al. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.10.016 · Cited by 149 · see citing works
Self-citationCayo, M. A., Cai, J., DeLaForest, A., Noto, F. K., Nagaoka, M., Clark, B. S., Collery, R. F., Si‐Tayeb, K., & Duncan, S. A. (2012) · Hepatology · doi:10.1002/hep.25871 · Cited by 148 · see citing works
Engrafted human stem cell–derived hepatocytes establish an infectious HCV murine model
Carpentier, A., Tesfaye, A., Chu, V., Nimgaonkar, I., Zhang, F., Lee, S. B., Thorgeirsson, S. S., Feinstone, S. M., & Liang, T. J. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75456 · Cited by 140 · 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
Rashidi, H., Luu, N. T., Alwahsh, S. M., Ginai, M., Alhaque, S., Dong, H., Tomaz, R. A., Vernay, B., Vigneswara, V., Hallett, J. M., et al. (2018) · Archives of Toxicology · doi:10.1007/s00204-018-2280-2 · Cited by 136 · see citing works
Self-citationDeveloping High-Fidelity Hepatotoxicity Models From Pluripotent Stem Cells
Medine, C. N., Lucendo‐Villarin, B., Storck, C., Wang, F., Szkolnicka, D., Khan, F., Pernagallo, S., Black, J. R., Marriage, H. M., Ross, J. A., et al. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2012-0138 · Cited by 136 · see citing works
Self-citationLiver Organoids: Recent Developments, Limitations and Potential
Harrison, S. P., Baumgarten, S., Verma, R., Lunov, O., Dejneka, A., & Sullivan, G. J. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.574047 · Cited by 141 · see citing works
Self-citationVosough, M., Omidinia, E., Kadivar, M., Shokrgozar, M. A., Pournasr, B., Aghdami, N., & Baharvand, H. (2013) · Stem Cells and Development · doi:10.1089/scd.2013.0088 · Cited by 132 · 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-citationDesmet, V. J. (2011) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-011-1048-3 · Cited by 126 · see citing works
Fernández-Checa, J. C., Bagnaninchi, P., Ye, H., Sancho‐Bru, P., Falcón‐Pérez, J. M., Royo, F., García‐Ruiz, C., Konu, Ö., Miranda, J. P., Lunov, O., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.06.021 · Cited by 129 · see citing works
Self-citationScalable production of tissue-like vascularized liver organoids from human PSCs
Harrison, S. P., Siller, R., Tanaka, Y., Chollet, M. E., de la Morena-Barrio, M. E., Xiang, Y., Patterson, B., Andersen, E., Bravo-Pérez, C., Kempf, H., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01074-1 · Cited by 119 · see citing works
Self-citationAsgari, S., Moslem, M., Lankarani, K. B., Pournasr, B., Miryounesi, M., & Baharvand, H. (2011) · Stem Cell Reviews and Reports · doi:10.1007/s12015-011-9330-y · Cited by 117 · see citing works
Cayo, M. A., Mallanna, S. K., Furio, F. D., Jing, R., Tolliver, L. B., Bures, M., Urick, A., Noto, F. K., Pashos, E. E., Greseth, M. D., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.01.011 · Cited by 115 · see citing works
Microengineered Liver Tissues for Drug Testing
Khetani, S. R., Berger, D. R., Ballinger, K. R., Davidson, M. D., Lin, C., & Ware, B. R. (2015) · SLAS Technology · doi:10.1177/2211068214566939 · Cited by 116 · see citing works
Reprogramming mammalian somatic cells.
Rodríguez-Osorio, N., Urrego, R., Cibelli, J., Eilertsen, K., & Memili, E. (2012) · Theriogenology · doi:10.1016/j.theriogenology.2012.05.030 · Cited by 101 · see citing works
Wang, B., Jakus, A. E., Baptista, P. M., Söker, S., Soto–Gutiérrez, A., Abecassis, M. M., Shah, R. N., & Wertheim, J. A. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0235 · Cited by 114 · see citing works
Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases
Kholodenko, I. V., & Yarygin, K. N. (2017) · BioMed Research International · doi:10.1155/2017/8910821 · Cited by 113 · see citing works
Lu, J., Einhorn, S., Venkatarangan, L., Miller, M., Mann, D. A., Watkins, P. B., & LeCluyse, E. L. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfv117 · Cited by 112 · see citing works
Generation of Multilayered 3D Structures of HepG2 Cells Using a Bio-printing Technique
Jeon, H., Kang, K., Park, S. A., Kim, W. D., Paik, S. S., Lee, S., Jeong, J., & Choi, D. (2016) · Gut and Liver · doi:10.5009/gnl16010 · Cited by 112 · see citing works
Chun, Y. S., Chaudhari, P., & Jang, Y.-Y. (2010) · International Journal of Biological Sciences · doi:10.7150/ijbs.6.796 · Cited by 107 · see citing works
Messina, A., Luce, E., Hussein, M., & Dubart‐Kupperschmitt, A. (2020) · Cells · doi:10.3390/cells9020420 · Cited by 111 · see citing works
Jenkins, M. J., & Farid, S. S. (2014) · Biotechnology Journal · doi:10.1002/biot.201400348 · Cited by 107 · see citing works
Du, C., Feng, Y., Qiu, D., Xu, Y., Pang, M., Cai, N., Xiang, A. P., & Zhang, Q. (2018) · Stem Cell Research & Therapy · doi:10.1186/s13287-018-0794-4 · Cited by 106 · see citing works
Accurate Prediction of Drug-Induced Liver Injury Using Stem Cell-Derived Populations
Szkolnicka, D., Farnworth, S. L., Lucendo‐Villarin, B., Storck, C., Zhou, W., Iredale, J. P., Flint, O. P., & Hay, D. C. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2013-0146 · Cited by 105 · see citing works
Self-citationThe potential of induced pluripotent stem cell derived hepatocytes
Hannoun, Z., Steichen, C., Dianat, N., Weber, A., & Dubart‐Kupperschmitt, A. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.02.025 · Cited by 103 · see citing works
Self-citationHuman pluripotent stem cells in drug discovery and predictive toxicology
Laustriat, D., Gide, J., & Peschanski, M. (2010) · Biochemical Society Transactions · doi:10.1042/bst0381051 · Cited by 100 · see citing works
Stem Cells in Liver Diseases and Cancer
Rountree, B. C., Mishra, L., & Willenbring, H. (2011) · Hepatology · doi:10.1002/hep.24762 · Cited by 101 · see citing works
Habka, D., Mann, D., Landes, R., & Soto–Gutiérrez, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0131764 · Cited by 99 · see citing works
New horizons for stem cell therapy in liver disease
Forbes, S. J., & Newsome, P. N. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.06.022 · Cited by 96 · see citing works
Self-citationBiologically inspired approaches to enhance human organoid complexity
Holloway, E. M., Capeling, M. M., & Spence, J. R. (2019) · Development · doi:10.1242/dev.166173 · Cited by 96 · see citing works
van Vliet, E. (2011) · ALTEX · doi:10.14573/altex.2011.1.017 · Cited by 95 · see citing works
Grant, R., Hallett, J. M., Forbes, S. J., Hay, D. C., & Callanan, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-42627-7 · Cited by 91 · see citing works
Self-citationCarpentier, A., Nimgaonkar, I., Chu, V., Xia, Y., Hu, Z., & Liang, T. J. (2016) · Stem Cell Research · doi:10.1016/j.scr.2016.03.009 · Cited by 90 · see citing works
Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells
Ma, X., Duan, Y., Tschudy-Seney, B., Roll, G. R., Behbahan, I. S., Ahuja, T. P., Tolstikov, V., Wang, C. X., McGee, J., Khoobyari, S., et al. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2012-0160 · Cited by 87 · see citing works
Generation of Multipotent Foregut Stem Cells from Human Pluripotent Stem Cells
Hannan, N. R. F., Fordham, R. P., Syed, Y. A., Moignard, V., Berry, A. A., Bautista, R., Hanley, N. A., Jensen, K. B., & Vallier, L. (2013) · Stem Cell Reports · doi:10.1016/j.stemcr.2013.09.003 · Cited by 86 · see citing works
Induced pluripotent stem cells and personalized medicine: current progress and future perspectives
Chun, Y. S., Byun, K., & Lee, B. (2011) · Anatomy & Cell Biology · doi:10.5115/acb.2011.44.4.245 · Cited by 86 · see citing works
Gao, X., & Liu, Y. (2017) · Cell Biology and Toxicology · doi:10.1007/s10565-017-9383-z · Cited by 83 · see citing works
Pettinato, G., Ramanathan, R., Fisher, R. A., Mangino, M. J., Zhang, N., & Wen, X. (2016) · Scientific Reports · doi:10.1038/srep32888 · Cited by 81 · see citing works
Józefczuk, J., Prigione, A., Chávez, L., & Adjaye, J. (2010) · Stem Cells and Development · doi:10.1089/scd.2010.0361 · Cited by 77 · see citing works
Behbahan, I. S., Duan, Y., Lam, A., Khoobyari, S., Ma, X., Ahuja, T. P., & Zern, M. Α. (2011) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9216-4 · Cited by 77 · see citing works
Olivier, E. N., Marenah, L., McCahill, A., Condie, A., Cowan, S., & Mountford, J. C. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0371 · Cited by 78 · see citing works
Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications
Yiangou, L., Ross, A., Goh, K. J., & Vallier, L. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.03.016 · Cited by 76 · see citing works
Sjogren, A.-K. M., Liljevald, M., Glinghammar, B., Sagemark, J., Li, X., Jonebring, A., Cotgreave, I. A., Brolén, G., & Andersson, T. B. (2014) · Archives of Toxicology · doi:10.1007/s00204-014-1265-z · Cited by 77 · see citing works
Kambal, A., Mitchell, G., Cary, W., Gruenloh, W., Jung, Y., Kalomoiris, S., Nacey, C., McGee, J., Lindsey, M., Fury, B., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.269 · Cited by 76 · see citing works
A Transcriptional Roadmap to the Induction of Pluripotency in Somatic Cells
Wang, Y., Mah, N., Prigione, A., Wolfrum, K., Andrade-Navarro, M. A., & Adjaye, J. (2010) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9137-2 · Cited by 76 · see citing works
The Interactions Between HBV and the Innate Immunity of Hepatocytes
Megahed, F. A. K., Zhou, X., & Sun, P. (2020) · Viruses · doi:10.3390/v12030285 · Cited by 76 · see citing works
Induced pluripotent stem cells: A new era for hepatology
Asgari, S., Pournasr, B., Salekdeh, G. H., Ghodsizadeh, A., Ott, M., & Baharvand, H. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.05.009 · Cited by 74 · see citing works
Pluripotent Stem Cell–Based Cancer Therapy: Promise and Challenges
Sharkis, S. J., Jones, R. J., Civin, C. I., & Jang, Y.-Y. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003920 · Cited by 77 · see citing works
Stem cell‐derived hepatocytes as a predictive model for drug‐induced liver injury: are we there yet?
Kia, R., Sison-Young, R. L. C., Heslop, J. A., Kitteringham, N. R., Hanley, N. A., MILLS, J. S., Park, B. K., & Goldring, C. E. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04360.x · Cited by 74 · see citing works
Bishi, D. K., Mathapati, S., Venugopal, J. R., Guhathakurta, S., Cherian, K. M., Ramakrishna, S., & Verma, R. S. (2013) · Journal of Materials Chemistry B · doi:10.1039/c3tb20241k · Cited by 74 · see citing works
Hepatoblast-Like Progenitor Cells Derived From Embryonic Stem Cells Can Repopulate Livers of Mice
Li, F., Liu, P., Liu, C., Xiang, D., Deng, L., Li, W., Wangensteen, K. J., Jianguo, S., Ma, Y., Hui, L., et al. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.08.042 · Cited by 72 · see citing works
Engineering Strategies for the Formation of Embryoid Bodies from Human Pluripotent Stem Cells
Pettinato, G., Wen, X., & Zhang, N. (2015) · Stem Cells and Development · doi:10.1089/scd.2014.0427 · Cited by 72 · see citing works
Pluripotent stem cell derived hepatocyte like cells and their potential in toxicity screening.
Greenhough, S., Medine, C. N., & Hay, D. C. (2010) · Toxicology · doi:10.1016/j.tox.2010.07.012 · Cited by 71 · see citing works
Self-citationYi, F., Liu, G., & Belmonte, J. C. I. (2012) · Protein & Cell · doi:10.1007/s13238-012-2918-4 · Cited by 71 · see citing works
Three-Dimensional Bioprinting of Hepatic Structures with Directly Converted Hepatocyte-Like Cells
Kang, K., Kim, Y., Jeon, H., Lee, S. B., Kim, J. S., Park, S. A., Kim, W. D., Yang, H. M., Kim, S. J., Jeong, J., et al. (2017) · Tissue Engineering Part A · doi:10.1089/ten.tea.2017.0161 · Cited by 70 · see citing works
Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis
Kwak, K.-A., Cho, H., Yang, J.-Y., & Park, Y. (2018) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2018/4197857 · Cited by 70 · see citing works
Kim, Y., Hong, S.-A., Yu, J., Eom, J., Jang, K., Yoon, S., Hong, D. H., Seo, D., Lee, S.-N., Woo, J., et al. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.04.010 · Cited by 70 · see citing works
Prospects For Stem Cell Transplantation in the Treatment of Hepatic Disease
Stutchfield, B. M., Forbes, S. J., & Wigmore, S. J. (2010) · Liver Transplantation · doi:10.1002/lt.22083 · Cited by 69 · see citing works
Self-citationYoshida, T., Takayama, K., Kondoh, M., Sakurai, F., Tani, H., Sakamoto, N., Matsuura, Y., Mizuguchi, H., & Yagi, K. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.007 · Cited by 67 · see citing works
Human induced pluripotent stem cell-derived hepatocytes for toxicology testing
Mann, D. A. (2014) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2015.981523 · Cited by 66 · see citing works
Standardization of pluripotent stem cell cultures for toxicity testing
Pistollato, F., Bremer‐Hoffmann, S., Healy, L. E., Young, L., & Stacey, G. N. (2012) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2012.639763 · Cited by 66 · see citing works
Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening
Baxter, M. A., Rowe, C., Alder, J. E., Harrison, S. P., Hanley, K. P., Park, B. K., Kitteringham, N. R., Goldring, C. E., & Hanley, N. A. (2010) · Stem Cell Research · doi:10.1016/j.scr.2010.02.002 · Cited by 66 · see citing works
Human Induced Pluripotent Stem Cells in Hepatology
Gerbal‐Chaloin, S., Funakoshi, N., Caillaud, A., Gondeau, C., Champon, B., & Si‐Tayeb, K. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.09.026 · Cited by 64 · see citing works
Iwao, T., Toyota, M., Miyagawa, Y., Okita, H., Kiyokawa, N., Akutsu, H., Umezawa, A., Nagata, K., & Matsunaga, T. (2013) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.dmpk-13-rg-005 · Cited by 63 · see citing works
Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests
Weber, S., & Gerbes, A. L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116049 · Cited by 64 · see citing works
A Cyclic AMP Analog, 8-Br-cAMP, Enhances the Induction of Pluripotency in Human Fibroblast Cells
Wang, Y., & Adjaye, J. (2010) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9209-3 · Cited by 62 · see citing works
Talamantes, S., Lisjak, M., Gilglioni, E. H., Llamoza-Torres, C. J., Ramos‐Molina, B., & Gurzov, E. N. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100811 · Cited by 60 · see citing works
Choudhury, Y., Toh, Y., Xing, J., Qu, Y., Poh, J., Li, H., Tan, H. S., Kanesvaran, R., Yu, H., & Tan, M. (2017) · Scientific Reports · doi:10.1038/srep41238 · Cited by 61 · see citing works
Human induced pluripotent stem cells—from mechanisms to clinical applications
Drews, K., Józefczuk, J., Prigione, A., & Adjaye, J. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0913-0 · Cited by 58 · see citing works
- Authors
- Sullivan, G. J., Hay, D. C., Park, I.-H., Fletcher, J., Hannoun, Z., Payne, C. M., Dalgetty, D., Black, J. R., Ross, J. A., Samuel, K., Wang, G., Daley, G. Q., Lee, J.-H., Church, G. M., Forbes, S. J., Iredale, J. P., & Wilmut, I.
- Affiliations
- Harvard University (US)
- MRC Centre for Regenerative Medicine (GB)
- Harvard Stem Cell Institute (US)
- Corresponding author
- Sullivan, Gareth J.
- Hay, David C.
- Park, In-Hyun
- ORCID
- Venue
- Hepatology
- Published
- 2010-01
- Volume
- 51
- Issue
- 1
- Pages
- 329-335
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2799548
- OpenAlex
- W2136607014
- Cited by
- 445
- References
- 13
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 6 · 2022: 8 · 2021: 12 · 2020: 21 · 2019: 25 · 2018: 32 · 2017: 33 · 2016: 37 · 2015: 36 · 2014: 21 · 2013: 46 · 2012: 57
- FWCI
- 21.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Scottish Funding Council
- Research Councils UK
- National Institutes of Health (DP1OD000256)
- Directorate for Biological Sciences
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- induced pluripotent stem cells, iPSC-derived hepatocytes, direct differentiation method, liver disease models, drug metabolism, CYP1A2, CYP3A4, sex differences, ethnic genetic variation, alpha-fetoprotein, albumin, fibrinogen, prealbumin, fibronectin, drug toxicology
- MeSH terms
- Cell Differentiation, Endoderm, Female, Humans, Liver, Male, Cell Culture Techniques, Cell Lineage, Induced Pluripotent Stem Cells
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