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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]
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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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BackgroundHighly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells
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Directed differentiation of human embryonic stem cells into functional hepatic cells†
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“…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 101–200 of 211
Robust expansion and functional maturation of human hepatoblasts by chemical strategy
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BackgroundThe Exciting Realities and Possibilities of iPS-Derived Cardiomyocytes
Takahashi, F., Patel, P., Kitsuka, T., & Arai, K. (2023) · Bioengineering · doi:10.3390/bioengineering10020237 · Cited by 13
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Stem Cells Treatment for Wilson Disease
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“To obtain hESC-Heps for clinical application, researchers continue to develop various methods to differentiate hESCs into hESC-Heps, such as using small molecules for differentiation to lower the cost [4,5], large-scale culture using a 3D suspension system or a rotating bioreactor [6,7], improving maturation by 3D-cul…”
Hoepfner, J., Kleinsorge, M., Papp, O., Ackermann, M., Alfken, S., Rinas, U., Solodenko, W., Kirschning, A., Sgodda, M., & Cantz, T. (2016) · Cell Biology International · doi:10.1002/cbin.10590 · Cited by 12
“…effects of small molecules, such as CHIR99021, are focused on immediate direct effects (Si-Tayeb et al. 2010; Touboul et al., 2010; Toivonen et al., 2013; Loh et al., 2014; Diekmann et al., 2015; Siller et al., 2015) but rather ignore the more long-term kinetics of the activated pathways.”
BackgroundResultInfluentialShi, D., Xin, J., Lu, Y., Ding, W., Jiang, J., Zhou, Q., Sun, S., Guo, B., Zhou, X., & Li, . (2020) · International Journal of Medical Sciences · doi:10.7150/ijms.36255 · Cited by 11
“These results are in agreement with previous studies of hepatic differentiation from hESCs, hiPSCs and hATSCs [10, 12, 17] and inferred hepatic conversion through the regulation of molecular pathways that control the lineage commitment of the MET process [11-13, 18, 19].”
ResultScalable production of tissue-like vascularised liver organoids from human PSCsPreprint
Harrison, S. P., Siller, R., Tanaka, Y., Xiang, Y., Patterson, B., Kempf, H., Melum, E., Åsrud, K. S., Chollet, M. E., Andersen, E. W., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.12.02.406835 · Cited by 11
Self-citationGao, X., Yourick, J. J., & Sprando, R. L. (2023) · The Journal of Toxicological Sciences · doi:10.2131/jts.48.441 · Cited by 10
Gania, Z., Noorintan, S. T., Septiari, N. P. D. P., Fitriany, D. S., & Torizal, F. G. (2022) · Future Pharmacology · doi:10.3390/futurepharmacol2030025 · Cited by 11
“Some effort has been made to minimize the requirements of these components, such as the development of growth factor-free differentiation protocols using small molecules [92].”
BackgroundTsang, H. Y., Lo, P. H. Y., & Lee, K. K. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.29.450347 · Cited by 10
“To validate the hepatic differentiation potentials of our hiPSC line, the cells were differentiated using a three-step protocol (9) first to definitive endoderms (DE) on day 2, then hepatoblasts (HB) on day 7 and finally into hepatocyte-like cells (HLC) on Day 21 (Fig.”
MethodStem Cell-Based Strategies: The Future Direction of Bioartificial Liver Development
Feng, L., Wang, Y., Fu, Y., Li, T., & He, G. (2024) · Stem Cell Reviews and Reports · doi:10.1007/s12015-023-10672-5 · Cited by 9
“To overcome these problems, some studies have been conducted using small molecules to simulate these growth factors and activate the corresponding signaling pathways [64, 84, 85].”
Female Reproductive Tract Organoids: Applications from Physiology to Pathology
Wang, X., Yang, D., & Peng, H. (2025) · Biomolecules · doi:10.3390/biom15070925 · Cited by 10
“Therefore, a study conducted experiments by combining biologics and small molecule drugs in organoid cultures and achieved positive results [107].”
From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease
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Automated Generation of hiPSC-Derived Hepatic Progeny by Cost-Efficient Compounds
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“Alterna-tively, DMSO has been used efficiently for inducing hepatic specification in iPSC-and ESC-based hepatocyte derivation strategies [10, 52].”
BackgroundMethodResultInfluentialThe potential of human induced pluripotent stem cells for modelling diabetic wound healing in vitro
Martin, P. E., O’Shaughnessy, E. M., Wright, C., & Graham, A. (2018) · Clinical Science · doi:10.1042/cs20171483 · Cited by 10
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Regulated differentiation of stem cells into an artificial 3D liver as a transplantable source
Chen, F., Wang, H., & Xiao, J. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2019.0022n · Cited by 8
Durumutla, H. B., Haller, A. M., Noble, G., Prabakaran, A. D., McFarland, K., Latimer, H., Rajput, A., Akinborewa, O., Namjou‐Khales, B., Hui, D. Y., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci190180 · Cited by 7
“…time points during the differentiation process: NANOG and OCT4 at the pluripotent stage (42); SOX17 and FOXA2 at the definitive endoderm stage (43); AFP and HNF1A at the immature hepatocyte stage (44); and ALB and CY18 , morphology, and albumin secretion at the mature hepatocyte stage (45).”
Effects of DMSO on the Pluripotency of Cultured Mouse Embryonic Stem Cells (mESCs)
Sousa, M. I., Correia, B., Branco, A. F., Rodrigues, A. S., & Ramalho‐Santos, J. (2020) · Stem Cells International · doi:10.1155/2020/8835353 · Cited by 7
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“CHIR9902 is a GSK3 β inhibitor that can activate Wnt/ β -catenin signaling pathway, which can replace Wnt3a and then initiate DE formation (21,43); LY294002 is the first synthetic inhibitor of the PI3K signal pathway.”
Pasqua, M., Gesù, R. D., Chinnici, C. M., Conaldi, P. G., & Francipane, M. G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158227 · Cited by 7
“Recently, a search for cost-effective protocols to support hepatoblast expansion with preserved bipotency has led to the establishment of a chemically defined culture medium consisting of a mixture of the TGF-β inhibitor A83-01, CHIR99021, the hepatocyte growth factor (HGF) receptor agonist N-hexanoic-Tyr-Ile-(6) amin…”
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Omics-Based Platform for Studying Chemical Toxicity Using Stem Cells
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Application of hiPSCs in tooth regeneration via cellular modulation
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“The differentiation protocol utilized was developed and optimized from the published literatures 18–21 , specifically chosen for its capacity to generate iHLOs with high CYP enzyme activity, particularly CYP3A4, which is crucial for drug metabolism and toxicology evaluations.”
Li, R., Zhao, Y., Yourick, J. J., Sprando, R. L., & Gao, X. (2022) · Biomedical Reports · doi:10.3892/br.2022.1526 · Cited by 5
“The role of DEX in hepatic maturation has been well established (8).”
BackgroundMethodInfluentialResearch progress in stem cell therapy for Wilson disease
Xiong, X., Gao, C., Meng, X., Liu, A., Gong, X., & Sun, Y. J. (2024) · Regenerative Therapy · doi:10.1016/j.reth.2024.03.005 · Cited by 5
“Several induction protocols have been used to differentiate iPSCs into hepatocyte-like cells (HLCs) that resemble PHHs and function as PHHs [67 e 69].”
BackgroundMethodCarberry, C. K., Ferguson, S., Beltrán, A. S., Fry, R. C., & Rager, J. E. (2022) · Toxicology in Vitro · doi:10.1016/j.tiv.2022.105412 · Cited by 8
Two Effective Routes for Removing Lineage Restriction Roadblocks: From Somatic Cells to Hepatocytes
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“dexamethasone, and dihexa) in a defined minimum medium without any of the exogenous growth factors necessary for hepatic specification promoted approximately 90% of iPSCs to HLCs [76,77].”
BackgroundYamashita, H., Fukuda, K., & Hattori, F. (2019) · JMA Journal · doi:10.31662/jmaj.2018-0042 · Cited by 5
Simple Maturation of Direct-Converted Hepatocytes Derived from Fibroblasts
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iPSCs for modeling hepatotropic pathogen infections
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Inner Ear Organoids: A Hydrogel-Based Platform for Drug Screening and Deafness Modeling
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Self-citationAn Efficient Method for Directed Hepatocyte-Like Cell Induction from Human Embryonic Stem Cells
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Homogeneous Differentiation of Functional Hepatocytes from Human Induced Pluripotent Stem Cells
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Parenteral nutrition emulsion inhibits CYP3A4 in an iPSC derived liver organoids testing platform
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Identification of NQO2 As a Protein Target in Small Molecule Modulation of Hepatocellular Function
Schepers, A. G., Shan, J., Cox, A. G., Huang, A. J., Evans, H. L., Walesky, C. M., Fleming, H. E., Goessling, W., & Bhatia, S. N. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00503 · Cited by 3
“Since DMSO can have effects on the differentiation of hepatic cells 14 , the DMSO concentration in media with and without FH1 was controlled for and never exceeded 0.1%.”
InfluentialGupta, S., Sharma, A., Paneerselvan, S., Kandoi, S., Patra, B., Bishi, D. K., & Verma, R. S. (2022) · Xenotransplantation · doi:10.1111/xen.12730 · Cited by 2
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“10 Also, Me 2 SO could affect the differentiation potential of human embryonic stem cells, 11 promote differentiation of human pluripotent stem cells, 12,13 and regulate osteoclast development in vitro .”
Effect of hypoxia on aquaporins and hepatobiliary transport systems in human hepatic cells
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“Assessment of maturity and functionality is typically assessed by the expression of definitive endoderm and hepatocyte markers, as well as the demonstration of crucial liver functions like cytochrome P450 enzyme activity, glycogen synthesis, albumin secretion, and drug processing [111–113].”
BackgroundDynamic regulation of EZH2 from HPSc to hepatocyte-like cell fate
Pistoni, M., Helsen, N., Vanhove, J., Boon, R., Xu, Z., Ordovás, L., & Verfaillie, C. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0186884 · Cited by 3
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Deschuyter, M., Martin, S., Salmanli, C., Hubsch, C., Vincent, A., Meignan, S., Furlan, A., Cosset, E. C., Burckel, H., Noël, G., et al. (2026) · Cancer and Metastasis Reviews · doi:10.1007/s10555-026-10316-3 · Cited by 1
“…and support the development of these large and highly specialized organoids, optimized culture media supplemented with appropriate growth factors are needed to induce proper differentiation, activity, and cellular communication, and must be adjusted throughout the culture steps [22, 23, 68–73].”
Clinical Application of Stem Cells in Liver Diseases: From Bench to Bedside
Xu, Y., & Zhang, Q. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812301-0.00015-3 · Cited by 1
Hosaka, K., Katsuda, T., Terai, S., & Ochiya, T. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812301-0.00005-0 · Cited by 1
Gao, X., Yourick, J. J., & Sprando, R. L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-823884-4.00003-1 · Cited by 1
Bertero, A., Coccini, T., & Caloni, F. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-99892-5.00022-0 · Cited by 1
Yamashita, H., & Hattori, F. (2023) · Journal of Visualized Experiments · doi:10.3791/65777 · Cited by 1
Kazmi, A., & Sultana, T. (2024) · Pharmacological Research - Reports · doi:10.1016/j.prerep.2024.100016 · Cited by 1
Reprogrammed Cell?based Therapy for Liver Disease: From Lab to Clinic
Mehdizadeh, A., & Darabi, M. (2017) · Journal of Renal and Hepatic Disorders · doi:10.15586/jrenhep.2017.6 · Cited by 1
Stem cell modeling of lipid genetics
Musunuru, K. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000490 · Cited by 1
Tauran, Y., Lereau, M., Ségard, B.-D., Danoy, M., Kimura, K., Shinohara, M., Brioude, A., Sakai, Y., de Jonge, H., Melnyk, O., et al. (2022) · Development Growth & Differentiation · doi:10.1111/dgd.12818 · Cited by 1
Gupta, R. (2021) · Research Publications (Maastricht University) · doi:10.26481/dis.20210304rg · Cited by 1
Yin, K., Yang, X., Wu, D., Yang, W., Dong, N., Li, N., & Zhao, R. C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.19.452852 · Cited by 1
“These two dedifferentiation methods have been reported in previous studies[22,23].”
ResultMitochondrial Dysfunction and Neuronal Anomalies in POLG Mutant Midbrain OrganoidsPreprint
Chen, A., Yangzom, T., Sullivan, G. J., & Liang, K. X. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.27.559684 · Cited by 1
“Fibroblast lines Detroit 551 and CCD-1079Sk were reprogrammed as disease-free controls iPSCs from Detroit 551 and CCD-1079Sk fibroblasts [19, 23, 24] .”
MethodSelf-citationYangzom, T., Chen, A., Sullivan, G. J., & Liang, K. X. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.08.566203 · Cited by 1
Self-citationMandal, A., Raju, S., & Viswanathan, C. (2016) · Cell Biology International · doi:10.1002/cbin.10649
“Various methods have been developed to direct human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into hepatocytes (Schwartz et al., 2005; Song et al., 2009; Touboul et al., 2010; Siller et al., 2015).”
MethodA Novel Method to Culture Hepatocytes
Haq, S. U. (2016) · TSpace (University of Toronto)
Nazareth, E. J. P. (2015) · TSpace (University of Toronto)
Romagnolli, P. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.10.2018.tde-31072018-161001
iPSCs for modeling familial hypercholesterolemia type II A
Caron, J., Dubart‐Kupperschmitt, A., & Weber, A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-822227-0.00010-7
Ncube, A., Graffmann, N., Greulich, J., Scherer, B., Wruck, W., & Adjaye, J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.09.447730
“370 The only problem arising from this approach is the ability to generate mature and functional iPSC371 derived hepatocyte-like cells which parallel liver-biopsy derived primary hepatocytes [34].”
BackgroundAlomari, M. (2021) · Stem cell biology and regenerative medicine · doi:10.1007/978-3-030-78101-9_6
Lefrak, S. S. (2005) · PubMed Central
Széky, B., Mayer, B., Gyongy, M., Hajdara, A., Barsi, S., Kárpáti, S., & Németh, K. (2021) · Folia Biologica · doi:10.14712/fb2021067050174
“Besides recombinantly expressed cytokines, small molecule pathway activators or inhibitors are also frequently used for hepatocyte differentiation (Siller et al., 2015).”
Széky, B., Mayer, B., Gyöngy, M., Hajdara, A., Barsi, S., Kárpáti, S., & Németh, K. (2023) · Folia Biologica · doi:10.14712/fb2023069010040
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947822
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947813
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947819
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947837
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947831
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947828
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947825
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947834
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020) · Figshare · doi:10.6084/m9.figshare.12947840
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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