Efficient and reproducible generation of human induced pluripotent stem cell-derived expandable liver organoids for disease modeling
Open accessAbstract
Genetic liver disease modeling is difficult because it is challenging to access patient tissue samples and to develop practical and relevant model systems. Previously, we developed novel proliferative and functional liver organoids from pluripotent stem cells; however, the protocol requires improvement for standardization and reproducible mass production. Here, we improved the method such that it is suitable for scalable expansion and relatively homogenous production, resulting in an efficient and reproducible process. Moreover, three medium components critical for long-term expansion were defined. Detailed transcriptome analysis revealed that fibroblast growth factor signaling, the essential pathway for hepatocyte proliferation during liver regeneration, was mainly enriched in proliferative liver organoids. Short hairpin RNA-mediated knockdown of FGFR4 impaired the generation and proliferation of organoids. Finally, glycogen storage disease type Ia (GSD1a) patient-specific liver organoids were efficiently and reproducibly generated using the new protocol. They well maintained disease-specific phenotypes such as higher lipid and glycogen accumulation in the liver organoids and lactate secretion into the medium consistent with the main pathologic characteristics of patients with GSD1a. Therefore, our newly established liver organoid platform can provide scalable and practical personalized disease models and help to find new therapies for incurable liver diseases including genetic liver diseases.
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iHLOs enable patient-specific modeling for precision medicine tailored to individual genetic and pathological conditions.
“Furthermore, iHLOs enable patient-specific modeling, providing a platform for precision medicine tailored to individual genetic and pathological conditions12,13.”
From Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology (2026) · cites this paper as [12]
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Cites
Vascularized and functional human liver from an iPSC-derived organ bud transplant
Takebe, T., Sekine, K., Enomura, M., Koike, H., Kimura, M., Ogaeri, T., Zhang, R.-R., Ueno, Y., Zheng, Y.-W., Koike, N., et al. (2013) · Nature · doi:10.1038/nature12271 · Cited by 2,170 · see citing works
Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver
Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M. M. A., Ellis, E., van Wenum, M., Fuchs, S. A., de Ligt, J., et al. (2015) · Cell · doi:10.1016/j.cell.2014.11.050 · Cited by 1,619 · see citing works
Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., et al. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1078-5 · Cited by 1,280 · see citing works
Sampaziotis, F., de Brito, M. C., Madrigal, P., Bertero, A., Saeb‐Parsy, K., Soares, F. A. C., Schrumpf, E., Melum, E., Karlsen, T. H., Bradley, J. A., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3275 · Cited by 398 · see citing works
Orchestrating liver development
Gordillo, M., Evans, T., & Gouon-Evans, V. (2015) · Development · doi:10.1242/dev.114215 · Cited by 375 · see citing works
Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids
Mun, S. J., Ryu, J., Lee, M., Son, Y. S., Oh, S. J., Cho, H., Son, M., Kim, S. J., Kim, S. J., Yoo, H. J., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.06.030 · Cited by 369 · see citing works
Self-citationOrganoids — Preclinical Models of Human Disease
Li, M., & Belmonte, J. C. I. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1806175 · Cited by 360 · see citing works
McCauley, H. A., & Wells, J. M. (2017) · Development · doi:10.1242/dev.140731 · Cited by 322 · see citing works
Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids
Marsee, A., Roos, F. J. M., Verstegen, M. M. A., Marsee, A., Roos, F., Verstegen, M., Clevers, H., Vallier, L., Takebe, T., Huch, M., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.04.005 · Cited by 310 · see citing works
Self-citationGlycogen storage disease type I and G6Pase-β deficiency: etiology and therapy
CHOU, J. Y., Jun, H. S., & Mansfield, B. C. (2010) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.189 · Cited by 233 · see citing works
Selzner, N., Selzner, M., Odermatt, B., Tian, Y., van Rooijen, N., & Clavien, P. (2003) · Gastroenterology · doi:10.1053/gast.2003.50098 · Cited by 201 · see citing works
Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic “power station”
Trapani, L. (2012) · World Journal of Hepatology · doi:10.4254/wjh.v4.i6.184 · Cited by 178 · see citing works
Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis
Kinoshita, T., Sekiguchi, T., Xu, M., Ito, Y., Kamiya, A., Tsuji, K.-I., Nakahata, T., & Miyajima, A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.13.7265 · Cited by 172 · see citing works
The C/EBP family of transcription factors in the liver and other organs
Takiguchi, M. (1998) · International Journal of Experimental Pathology · doi:10.1046/j.1365-2613.1998.00082.x · Cited by 129 · see citing works
Lei, K. J., Shelly, L. L., Lin, B., Sidbury, J. B., Chen, Y. T., Nordlie, R. C., & CHOU, J. Y. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117645 · Cited by 109 · see citing works
Padrissa‐Altés, S., Bachofner, M., Bogorad, R. L., Pohlmeier, L. M., Rossolini, T., Böhm, F., Liebisch, G., Hellerbrand, C., Koteliansky, V., Speicher, T., et al. (2014) · Gut · doi:10.1136/gutjnl-2014-307874 · Cited by 98 · see citing works
Markers of liver regeneration—the role of growth factors and cytokines: a systematic review
Hoffmann, K., Nagel, A. J., Tanabe, K., Fuchs, J., Dehlke, K., Ghamarnejad, O., Lemekhova, A., & Mehrabi, A. (2020) · BMC Surgery · doi:10.1186/s12893-019-0664-8 · Cited by 94 · see citing works
Flodby, P., Antonson, P., Barlow, C., Blanck, A., Porsch-Hällström, I., & Xanthopoulos, K. G. (1993) · Experimental Cell Research · doi:10.1006/excr.1993.1244 · Cited by 88 · see citing works
Liver transplantation for glycogen storage disease type Ia
Reddy, S. K., Austin, S. L., Spencer‐Manzon, M., Koeberl, D. D., Clary, B. M., Desai, D. M., Smith, A. D., & Kishnani, P. S. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.05.026 · Cited by 76 · see citing works
Kim, D., Ryu, J., Son, M., Oh, J., Chung, K., Lee, S., Lee, J., Ahn, J., Min, J., Ahn, J., et al. (2017) · Hepatology · doi:10.1002/hep.29324 · Cited by 75 · see citing works
Self-citationCross-talk between the Androgen Receptor and the Liver X Receptor
Krycer, J. R., & Brown, A. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.227082 · Cited by 71 · see citing works
The glycolytic pathway in adult liver fluke, Fasciola hepatica
Prichard, R. K., & Schofield, P. J. (1968) · Comparative Biochemistry and Physiology · doi:10.1016/0010-406x(68)90783-4 · Cited by 68 · see citing works
Probst, I., & Unthan‐Fechner, K. (1985) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1985.tb09309.x · Cited by 53 · see citing works
Twaroski, K., Mallanna, S. K., Jing, R., Furio, F. D., Urick, A., & Duncan, S. A. (2015) · Genes & Development · doi:10.1101/gad.268961.115 · Cited by 52 · see citing works
Human liver model systems in a dish
Thompson, W. L., & Takebe, T. (2021) · Development Growth & Differentiation · doi:10.1111/dgd.12708 · Cited by 49 · see citing works
Prasajak, P., & Leeanansaksiri, W. (2013) · Stem Cells International · doi:10.1155/2013/762196 · Cited by 44 · see citing works
Dong, J., Fujii, S., Li, H., Nakabayashi, H., Sakai, M., Nishi, S., Goto, D., Furumoto, T., Imagawa, S., Zaman, T., et al. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000159701.24372.49 · Cited by 36 · see citing works
Hormonal Contribution to Liver Regeneration
Rmilah, A. A. A., Zhou, W., & Nyberg, S. L. (2020) · Mayo Clinic Proceedings Innovations Quality & Outcomes · doi:10.1016/j.mayocpiqo.2020.02.001 · Cited by 34 · see citing works
Long-Term Expansion of Functional Human Pluripotent Stem Cell-Derived Hepatic Organoids
Mun, S. J., Hong, Y.-H., Ahn, H.-S., Ryu, J., Chung, K., & Son, M. J. (2020) · International Journal of Stem Cells · doi:10.15283/ijsc20060 · Cited by 33 · see citing works
Self-citationChallenges of Gene Therapy for the Treatment of Glycogen Storage Diseases Type I and Type III
Jauze, L., Monteillet, L., Mithieux, G., Rajas, F., & Ronzitti, G. (2019) · Human Gene Therapy · doi:10.1089/hum.2019.102 · Cited by 29 · see citing works
Brooks, E. D., Landau, D. J., Everitt, J. I., Brown, T. T., Grady, K. M., Waskowicz, L. R., Bass, C. R., D'Angelo, J., Asfaw, Y. G., Williams, K. D., et al. (2018) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-018-0223-y · Cited by 29 · see citing works
Directed hepatic differentiation from embryonic stem cells
Chen, X., & Zeng, F. (2011) · Protein & Cell · doi:10.1007/s13238-011-1023-4 · Cited by 21 · see citing works
Recent development and gene therapy for glycogen storage disease type Ia
CHOU, J. Y., Kim, G., & Cho, J. (2017) · Liver Research · doi:10.1016/j.livres.2017.12.001 · Cited by 17 · see citing works
Fearon, A. E., Slabber, C. F., Kuklin, A., Bachofner, M., Tortola, L., Pohlmeier, L. M., Pantasis, S., Hornemann, T., Chen, L., Köpf, M., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103143 · Cited by 14 · see citing works
Kim, J.-H., Mun, S. J., Kim, J., Son, M. J., & Kim, S. (2023) · iScience · doi:10.1016/j.isci.2023.107675 · Cited by 13 · see citing works
Self-citationStubbs, A., Engelman, J. L., Walker, J. I., Faik, P., Murphy, G. M., & Wilkinson, M. (1994) · Gut · doi:10.1136/gut.35.5.683 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kimura, H., Nishikawa, M., Kutsuzawa, N., Tokito, F., Kobayashi, T., Kurniawan, D. A., Shioda, H., Cao, W., Shinha, K., Nakamura, H., et al. (2024) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2024.101046 · Cited by 61 · see citing works
Patient-derived tumor organoids: A preclinical platform for personalized cancer therapy
Taurin, S., Alzahrani, R., Aloraibi, S., Ashi, L., AlHarmi, R. A. R., & Hassani, N. (2024) · Translational Oncology · doi:10.1016/j.tranon.2024.102226 · Cited by 54 · see citing works
Hong, S. E., Mun, S. J., Lee, Y. J., Yoo, T., Suh, K., Kang, K. W., Son, M. J., Kim, W. K., & Choi, M. (2025) · Nature Genetics · doi:10.1038/s41588-025-02237-8 · Cited by 30 · see citing works
Self-citationAdvances in liver and pancreas organoids: how far we have come and where we go next
Sljukic, A., Jenkinson, J. G., Niksic, A., Prior, N., & Huch, M. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01116-1 · Cited by 23 · see citing works
Validating Well-Functioning Hepatic Organoids for Toxicity Evaluation
Choi, S. Y., Kim, T. H., Kim, M. J., Mun, S. J., Kim, T., Jung, K. K., Oh, I. U., Oh, J. H., Son, M. J., & Lee, J. H. (2024) · Toxics · doi:10.3390/toxics12050371 · Cited by 14 · see citing works
Self-citationGong, D., Mo, J., Zhai, M., Zhou, F., Wang, G., Ma, S., Dai, X., & Deng, X. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2024.1521851 · Cited by 11 · see citing works
Wang, L., Chen, A., Zhang, D., & He, Z. (2025) · Cells · doi:10.3390/cells14231898 · Cited by 8 · see citing works
Biomedical applications of organoids in genetic diseases
Huang, W., Jeong, S., Kim, W., & Chen, L. (2024) · Medical Review · doi:10.1515/mr-2024-0077 · Cited by 7 · see citing works
Regenerative human liver organoids (HLOs) in a pillar/perfusion plate for hepatotoxicity assaysPreprint
Shrestha, S., Acharya, P., Kang, S. Y., Vanga, M. G., Lekkala, V. K. R., Liu, J., Yang, Y. S., Joshi, P., & Lee, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.25.586638 · Cited by 6 · see citing works
Yang, S., Hao, J., Ooka, M., & Xia, M. (2026) · Scientific Reports · doi:10.1038/s41598-025-32539-0 · Cited by 5 · see citing works
Applications and limitations of pluripotent stem cell-derived liver organoids
Feng, Z., Zhou, B., Shuai, Q., Mu, J., & Xie, J. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003707 · Cited by 5 · see citing works
Physiological Relevant 3D Biomanufacturing of Pluripotent Stem Cells for Regenerative Medicine
Sun, X. S., Zhang, Y. S., & Atala, A. (2025) · Current Stem Cell Reports · doi:10.1007/s40778-025-00250-5 · Cited by 3 · see citing works
Revolutionising oral organoids with artificial intelligence.
Yang, J., Fischer, N. G., & Ye, Z. (2024) · PubMed Central · doi:10.12336/biomatertransl.2024.04.004 · Cited by 4 · see citing works
Organoids in Genetic Disorders: from Disease Modeling to Translational Applications
Zhu, Y., Lin, N., Li, J., Zhang, H., Zhang, P., Cheng, X., Yang, Q., & Liu, L. (2025) · Stem Cell Reviews and Reports · doi:10.1007/s12015-025-10973-x · Cited by 2 · see citing works
Wu, Y., Wang, Y., Zhang, W., Yuan, L.-L., & Chen, Y. (2026) · Stem Cell Research & Therapy · doi:10.1186/s13287-026-05080-8 · Cited by 2 · see citing works
Panchuk, I., Kovalskaia, V. A., Balinova, N., Рыжкова, О. П., & Smirnikhina, S. (2025) · Biology · doi:10.3390/biology14060586 · Cited by 2 · see citing works
Ogawa, M., Liu, J. C., Dadvar, A., Tian, B., Zhao, X., Fernandes, I., Minegishi, K., Takase, K., Cui, C., Hernandez, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.13.659636 · Cited by 2 · see citing works
Advanced strategies in organoids for metabolic monitoring and metabolic disease modeling
Ma, W., Xu, Y., Gu, Z., & Li, D. (2025) · Nano Research · doi:10.26599/nr.2025.94907988 · Cited by 1 · see citing works
Na, H.-J., Shin, Y., Kim, S.-H., Jang, S. P., Son, M. J., Choi, Y. M., Jeon, H. G., Kwon, O.-S., & Chung, K. (2025) · PLoS ONE · doi:10.1371/journal.pone.0336164 · Cited by 1 · see citing works
Self-citationHong, S. E., Mun, S. J., Lee, Y. J., Yoo, T., Suh, K., Kang, K. W., Son, M. J., Kim, W. S., & Choi, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.20.614203 · Cited by 1 · see citing works
Self-citationLiver Systems in Safety Pharmacology
Mahajan, V. (2024) · Springer eBooks · doi:10.1007/978-3-030-73317-9_64-1
Liver Systems in Safety Pharmacology
Mahajan, V. (2024) · Springer eBooks · doi:10.1007/978-3-031-35529-5_64
Na, H.-J., Shin, Y., Kim, S.-H., Jang, S. P., Son, M. J., Choi, Y. M., Jeon, H. G., Kwon, O.-S., & Chung, K. (2025) · doi:10.17504/protocols.io.4r3l29mjjv1y/v2
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Kim, M. J., Choi, S. Y., Youn, S. M., Kim, T. G., Oh, I. U., Park, S. A., Oh, J. H., Son, M. J., & Lee, J. H. (2026) · Frontiers in Toxicology · doi:10.3389/ftox.2026.1805474
Self-citationZhou, Y., Zeng, M., Fu, G., & Gao, Y. (2026) · Stem Cell Reviews and Reports · doi:10.1007/s12015-026-11172-y
Zhou, X., Yan, X., Zhang, Z., Zhang, Z., Que, Y., Wang, Y., Zhang, Y., Lu, K., & Wang, L. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1890385
Yang, Y., Dastjerd, M. K., Smout, A., Merens, V., Toprakhisar, B., Verfaillie, C. M., Chesné, C., & van Grunsven, L. A. (2026) · Cells · doi:10.3390/cells15171556
- Authors
- Mun, S. J., Hong, Y.-H., Shin, Y., Lee, J., Cho, H.-S., Kim, D.-S., Chung, K.-S., & Son, M. J.
- Affiliations
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Corresponding author
- Chung, Kyung-Sook
- Son, Myung Jin
- Venue
- Scientific Reports
- Published
- 2023-12-22
- Volume
- 13
- Issue
- 1
- Pages
- 22935-22935
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC10739970
- OpenAlex
- W4390079775
- Cited by
- 28
- References
- 36
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 9
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Korea Research Institute of Bioscience and Biotechnology (KGM5362313, KGM4722331)
- National Research Foundation of Korea (NRF- 2022R1A2B5B02001644)
- Ministry of Food and Drug Safety (22213MFDS386)
- Ministry of Trade, Industry and Energy (20009774)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- liver organoids, induced pluripotent stem cells, disease modeling, hereditary liver disease, glycogen storage disease type Ia, FGFR4, FGF signaling, hepatocyte proliferation, gene expression profiling, personalized medicine, liver regeneration
- MeSH terms
- Cell Differentiation, Glycogen Storage Disease Type I, Humans, Liver, Liver Diseases, Organoids, Induced Pluripotent Stem Cells
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