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Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids
Open accessAbstract
The mammalian liver possesses a remarkable regenerative ability. Two modes of damage response have been described: (1) The "oval cell" response emanates from the biliary tree when all hepatocytes are affected by chronic liver disease. (2) A massive, proliferative response of mature hepatocytes occurs upon acute liver damage such as partial hepatectomy (PHx). While the oval cell response has been captured in vitro by growing organoids from cholangiocytes, the hepatocyte proliferative response has not been recapitulated in culture. Here, we describe the establishment of a long-term 3D organoid culture system for mouse and human primary hepatocytes. Organoids can be established from single hepatocytes and grown for multiple months, while retaining key morphological, functional and gene expression features. Transcriptional profiles of the organoids resemble those of proliferating hepatocytes after PHx. Human hepatocyte organoids proliferate extensively after engraftment into mice and thus recapitulate the proliferative damage-response of hepatocytes.
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“the formation of organoids also recapitulate a 3D in vivo‐like microenvironment that may well compensate for the lack of structural support for tissue formation in the damaged extracellular matrix environment when used as xenografts.[ 18 , 19 ]”
From Sweat Gland Organoids Originating from Reprogrammed Epidermal Keratinocytes Functionally Recapitulated Damaged Skin (2021) · cites this paper as [19]
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“Hu et al. demonstrated that hepatocyte-derived organoids undergo an initial 30-day quiescent phase post-transplantation, succeeded by rapid and extensive liver repopulation akin to that of PHs [16].”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [16]
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“We further demonstrate the versatility and flexibility of multiplexed CRISPR base-editing for cancer modeling across several epithelial tissues by mutating liver, endometrium, and organoids32–34.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [33]
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“Furtherly, functional intestinal organoids exhibit a relatively thick mucus layer due to mucus secretion from mature goblet cells122, which can be detected by Alcian blue (AB) and periodic acid-Schiff (PAS) staining123,124.”
From Organoids (2022) · cites this paper as [124]
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InfluentialOrganoids for the Study of Liver Cancer
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BackgroundToward better drug development: Three-dimensional bioprinting in toxicological research
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Morrison, M. A., Artru, F., Trovato, F. M., Triantafyllou, E., & McPhail, M. J. W. (2023) · Liver International · doi:10.1111/liv.15545 · Cited by 22
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Medicinal Biotechnology for Disease Modeling, Clinical Therapy, and Drug Discovery and Development
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BackgroundInfluentialTransformational Applications of Human Cardiac Organoids in Cardiovascular Diseases
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MethodWhat gastroenterologists and hepatologists should know about organoids in 2019
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BackgroundFucoxanthin Attenuates Inflammation via Interferon Regulatory Factor 3 (IRF3) to Improve Sepsis
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Using Liver Organoids as Models to Study the Pathobiology of Rare Liver Diseases
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“For example, cholangiocytes express the KRT19, KRT7, and SOX9 genes, while hepatocytes express the ALB, HNF4A, and MRP4 genes [31].”
BackgroundHu, H., Sun, C., Chen, J., & Li, Z. (2024) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-024-05654-0 · Cited by 20
“Therefore, to guarantee the stability and dependability of organoid culture and application, it is imperative to carefully regulate the number of passages (Hu et al. 2018; Yamamoto et al. 2017).”
BackgroundSelf-citationCold-induced FOXO1 nuclear transport aids cold survival and tissue storage
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“Interestingly, no significant dedifferentiation to a progenitor state was observed during this process (Nuciforo and Heim, 2021) Based on the reparative mechanism of acute liver injury, mature hepatocyte-derived liver organoids can be generated directly, cultured and expanded in vitro for long periods of time (Hu et a…”
BackgroundAdvancing hepatotoxicity assessment: current advances and future directions
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Sequential drug delivery for liver diseases
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Use of human tissue stem cell-derived organoid cultures to model enterohepatic circulation
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Organoids as research models for hepatocellular carcinoma
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Research progress and application of liver organoids for disease modeling and regenerative therapy
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“In 2018, Hu et al. [60] established a long-term culture system for mouse and human primary liver cells to generate hepatocyte orga-noids.”
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“This experiment was approved by the Institutional Animal Care and Use Committee (IACUC) of the Institute of Medical Laboratory Animals and Medical School, University of Chinese Academy of Sciences.”
MethodEmerging biotechnologies for engineering liver organoids
Zhao, J., Zhi, Y., Ren, H., Wang, J., & Zhao, Y. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.11.002 · Cited by 19
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Design principles and therapeutic applications of novel synthetic WNT signaling agonists
Post, Y., Lu, C., Fletcher, R. B., Yeh, W., Nguyen, H., Lee, S., & Li, Y. (2024) · iScience · doi:10.1016/j.isci.2024.109938 · Cited by 18
Ariño, S., Ferrer‐Lorente, R., Serrano, G., Zanatto, L., de la Torre, R. A. M. G., Gratacós‐Ginès, J., Rubio, A. B., Pérez-Guasch, M., Mateos-Sánchez, C., Aguilar‐Bravo, B., et al. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.07.014 · Cited by 19
de Lau, W. B. M., Wijnakker, J. J. A. P. M., van Son, G. J. F., Krueger, D., Wang, D., Abendroth, M. S., Schreurs, R., Janda, C. Y., van Rijt, F. L. H., Chalopin, B., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02874-8 · Cited by 23
“…of intestinal organoids in BME also held for organoids derived from other regions of the human gastrointestinal tract: duodenum ( N = 2), J2 jejunum ( N = 2) and N39 ileum ( N = 2), stomach organoids 31 ( N = 1) and ductal-type organoids from the pancreas 32 ( N = 2) and liver 33 ( N = 2).”
Self-citationSun, R., Jiao, D., Yuan, W., Wang, H., Ren, L., Fu, Z., Zhang, J., Yue, X., Wu, Z., Li, C., et al. (2026) · Nature Metabolism · doi:10.1038/s42255-025-01430-7 · Cited by 21
“Human hepatocyte-organoid (Hep-Org) was generated as described previously 54 .”
Self-citationPTEN-mediated AKT/β-catenin signaling enhances the proliferation and expansion of Lgr5+ hepatocytes
Han, J., Lin, K., Zhang, X., Yan, L., Liu, J., & Liu, J. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.56091 · Cited by 16
“At present, in vitro culture systems that generate liver organoid from isolated mouse Lgr5+ hepatocytes have been established [25], and long-term culture and large-scale amplification of liver organoids have also been achieved [27].”
BackgroundIwasawa, K., & Takebe, T. (2021) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2021.06.007 · Cited by 19
Negoro, R., Tasaka, M., Deguchi, S., Takayama, K., & Fujita, T. (2022) · Cells · doi:10.3390/cells11101677 · Cited by 16
Kim, H. J., Kim, G., Chi, K. Y., & Kim, J. (2022) · International Journal of Stem Cells · doi:10.15283/ijsc22154 · Cited by 17
“This strategy has been used to generate several types of liver organoids from liver-resident cells, including epithelial cell adhesion molecule (EpCAM)-positive ductal cells (7) and primary hepatocytes (8), and human pluripotent stem cells (hPSCs) (9-11).”
MethodOrganoids as a model to study intestinal and liver dysfunction in severe malnutrition
Horcas‐Nieto, J. M., Versloot, C. J., Langelaar‐Makkinje, M., Gerding, A., Blokzijl, T., Koster, M. H., Baanstra, M., Martini, I. A., Coppes, R. P., Bourdon, C., et al. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166635 · Cited by 15
“Organoids have the advantages of cell culture – ease of sampling and control of nutrient concentrations – while maintaining broader functionality of the modelled organ [33,34].”
BackgroundDing, M., Huang, W., Liu, G., Zhai, B., Yan, H., & Zhang, Y. (2023) · BMC Genomics · doi:10.1186/s12864-023-09349-7 · Cited by 16
Hyperplastic Human Macromass Cartilage for Joint Regeneration
Wen, Y., Chen, Y., Wu, W., Zhang, H., Peng, Z., Yao, X., Zhang, X., Jiang, W. M., Liao, Y., Xie, Y., et al. (2023) · Advanced Science · doi:10.1002/advs.202301833 · Cited by 15
Post, Y., Dilip, A., Xie, L., Sura, A., Suen, N., Ye, J., Mutha, D., Liu, A. T., Nguyen, H., Whisler, E., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.006 · Cited by 16
Engineering prostate cancer in vitro: what does it take?
Buskin, A., Scott, E., Nelson, R., Gaughan, L., Robson, C. N., Heer, R., & Hepburn, A. C. (2023) · Oncogene · doi:10.1038/s41388-023-02776-6 · Cited by 17
“Hepatocyte organoids have been successfully generated, whilst iPSC technology has enabled development of multilineage liver organoids incorporating many non-parenchymal cells and also a vasculature [96, 97].”
BackgroundZhang, X., Xie, G., Ma, H., Ding, S., Wu, Y., Fei, Y., Cheng, Q., Huang, Y., & Wang, Y. (2023) · Biofabrication · doi:10.1088/1758-5090/acee21 · Cited by 19
The Crosstalk between Mesenchymal Stromal/Stem Cells and Hepatocytes in Homeostasis and under Stress
Kholodenko, I. V., Kholodenko, R. V., & Yarygin, K. N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015212 · Cited by 16
Inhibition of CYP1A1 Alleviates Colchicine-Induced Hepatotoxicity
Huang, R., Duan, J., Huang, W. C., Cheng, Y., Zhu, B., & Li, F. (2024) · Toxins · doi:10.3390/toxins16010035 · Cited by 16
“Quantitative real-time PCR analysis, immunohistochemistry and Western blot analysis are described in Supporting Information [42–44].”
MethodYang, H., Niu, S., Guo, M.-H., & Xue, Y. (2024) · Archives of Toxicology · doi:10.1007/s00204-024-03777-4 · Cited by 18
“The 3D organoids can also simulate many different types of human tissue structures, such as the brain (Lancaster et al. 2013), liver (Hu et al. 2018), lung (Miller et al. 2019), and skin (Ebner-Peking et al. 2021).”
Yang, H., Li, J., Zheng, Y. K., Cao, Y., Zhu, Y., Sang, G., Galan, E. A., Ruan, C., Ma, W. M. J., Dai, X., et al. (2024) · Device · doi:10.1016/j.device.2024.100420 · Cited by 16
Self-citationTransSynW: A single-cell RNA-sequencing based web application to guide cell conversion experiments
Ribeiro, M. M., Okawa, S., & del Sol, A. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.20-0227 · Cited by 15
“27 Next, the scRNA-seq data of organoid 28 and in vivo hep-tocytes 28-30 were analyzed.”
MethodEffect of mesenchymal stem cell in liver regeneration and clinical applications
Lee, S. M., Lee, S. D., Wang, S. Z., Sarkar, D., Lee, H. M., Khan, A. A., Bhati, C. S., Sharma, A., Kumaran, V., Bruno, D. A., et al. (2021) · Hepatoma Research · doi:10.20517/2394-5079.2021.07 · Cited by 17
Requena, D., Medico, J. A., Soto, L. F., Shirani, M., Saltsman, J. A., Torbenson, M. S., Coffino, P., & Simon, S. M. (2024) · Nature Communications · doi:10.1038/s41467-024-55238-2 · Cited by 17
Ge, Y., Yang, S., Zhang, T., Luo, K., Zhang, J., Wei, Y., Pu, Y., Chen, Z., & Liang, G. (2025) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2025.118215 · Cited by 15
Tissue regeneration: Unraveling strategies for resolving pathological fibrosis
Li, J., Wang, S., Yuan, J., Mao, X., Wang, X., Zhang, L., Dong, Q., Chen, Z., Wang, Y., & Tang, N. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.10.002 · Cited by 19
Modeling immune lineage co-development in human pluripotent stem cell-derived liver organoids
Rezvani, M., Quach, S., Lewis, K., Saiki, N., Xue, C., Kimura, M., Iwasawa, K., Weihs, J., Elzobair, T., Reza, H. A., et al. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.11.018 · Cited by 18
A Perspective on a Urine-Derived Kidney Tubuloid Biobank from Patients with Hereditary Tubulopathies
Schutgens, F., Rookmaaker, M. B., & Verhaar, M. C. (2021) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2020.0366 · Cited by 14
Progress and perspective of organoid technology in cancer-related translational medicine
Lin, Y., Jiang, L., He, Q., Yuan, M., & Cao, J. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112869 · Cited by 18
Otumala, A. E., Hellen, D. J., Luna, C. A., Delgado, P., Dissanayaka, A., Ugwumadu, C., Oshinowo, O. T., Islam, M. M., Shen, L., Karpen, S. J., et al. (2023) · Lab on a Chip · doi:10.1039/d2lc00940d · Cited by 17
Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase
Darmasaputra, G., Geerlings, C. C., Lopes, S. M. C. D. S., Clevers, H. C., & Galli, M. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202403020 · Cited by 16
“…and non-canonical M phases in human hepatocytes; however, our attempts to grow Hep-Org lines with different concentrations of insulin or in a growth medium that diminishes fetal-like properties of hepatocytes (Hu et al., 2018) did not result in an increase in the percentage of binucleated cells.”
BackgroundMethodInfluentialSelf-citationEx Vivo Tools and Models in MASLD Research
Velliou, R.-I., Giannousi, E., Ralliou, C., Kassi, E., & Chatzigeorgiou, A. (2024) · Cells · doi:10.3390/cells13221827 · Cited by 15
“Hep-orgs proliferate much slower and double every 5–7 days if derived from fetal livers or are passaged 1–2 times every 50–75 days if derived from adult livers [72].”
Controlled Apoptosis of Stromal Cells to Engineer Human Microlivers
Chen, A. X., Chhabra, A., Song, H. G., Fleming, H. E., Chen, C. S., & Bhatia, S. N. (2020) · Advanced Functional Materials · doi:10.1002/adfm.201910442 · Cited by 15
Lee, H., Im, J. S., Choi, D. B., & Woo, D. (2021) · Organoid · doi:10.51335/organoid.2021.1.e11 · Cited by 17
“Orthotopic transplantation of liver organoids demonstrated that human fetal hepatocyte organoids displayed high engraftment efficiency in a toxin-induced acute liver failure mouse model [76].”
BackgroundSimão, D. F., Gomes, C. M., Alves, P. M., & Brito, C. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107883 · Cited by 15
Dhakal, B., Li, C. M. Y., Li, R., Yeo, K. K. L., Wright, J. A., Gieniec, K. A., Vrbanac, L., Sammour, T., Lawrence, M. J., Thomas, M., et al. (2022) · Cancers · doi:10.3390/cancers14041043 · Cited by 15
“Patientderived organoid cultures have been recently shown to retain their tissue identity from both normal liver and colorectal cancer tissues [30,31].”
BackgroundEstablishing Human Lung Organoids and Proximal Differentiation to Generate Mature Airway Organoids
Li, C., Chiu, M. C., Yu, Y., Liu, X., Xiao, D., Huang, J., Wan, Z., & Zhou, J. (2022) · Journal of Visualized Experiments · doi:10.3791/63684 · Cited by 19
Wu, H., Wang, J., Liu, S., Wang, Y., Tang, X., Xie, J., Wang, N., Shan, H., Chen, S., Zhang, X., et al. (2025) · Cell Proliferation · doi:10.1111/cpr.70001 · Cited by 16
“Owing to the limitations of PHHs in availability and genetic heterogenicity among different donors, it is still challenging to apply it into pharmaceutical industry and clinical applications [14].”
Huang, T. H., Huang, W. T., & Bian, Q. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114222 · Cited by 14
Metadata
- Authors
- Hu, H., Gehart, H., Artegiani, B., LÖpez-Iglesias, C., Dekkers, F., Basak, O., van Es, J., Chuva de Sousa Lopes, S. M., Begthel, H., Korving, J., van den Born, M., Zou, C., Quirk, C., Chiriboga, L., Rice, C. M., Ma, S., Rios, A., Peters, P. J., de Jong, Y. P., & Clevers, H.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Weill Cornell Medicine (US)
- Rockefeller University (US)
- NYU Langone Health (US)
- University of Hong Kong (HK)
- Princess Máxima Center (NL)
- Maastricht University (NL)
- Corresponding author
- Clevers, Hans
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 175
- Issue
- 6
- Pages
- 1591-1606.e19
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2903148550
- Cited by
- 837
- References
- 68
- Citations by year
- 2026: 74 · 2025: 114 · 2024: 141 · 2023: 122 · 2022: 118 · 2021: 134 · 2020: 95 · 2019: 38 · 2018: 1
- FWCI
- 41.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- MKMD (114021012)
- Netherlands Organization for Scientific Research (NWO-ZonMw
- Koerber Foundation
- National Natural Science Foundation of China (31501179)
- Foundation for Outstanding Young Scientist in Shandong Province (BS2014SW004)
- Future Scientist Program of Chinese Scholarship Council (CSC
- NWO-ZonMW (016.166.119)
- NWO/VENI (863.15.015)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- hepatocyte organoids, 3D organoid culture, primary hepatocytes, partial hepatectomy, hepatocyte proliferation, liver regeneration, cholangiocytes, engraftment, mouse hepatocytes, human hepatocytes
- MeSH terms
- Animals, Cells, Cultured, Humans, Mice, Inbred BALB C, Organoids, Stem Cells, Time Factors, Mice, Knockout, Cell Culture Techniques, Hepatocytes, Cell Proliferation, Mice
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