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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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“However, change in culture conditions can induce the expression of periportal hepatocyte markers [34] and trans-differentiation into chol-angiocytes [33], indicating that hepatocyte organoids exhibit high plasticity.”
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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
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“Mouse organoids (Hu et al., 2018; Lee et al., 2020; Taguchi and Nishinakamura, 2017), on the other hand, are generated from ESC or iPSC stable lines, eliminating the need to isolate ESCs from embryos for each differentiation.”
Qin, C., Wu, H., Liao, P., Yan, W., Shi, X., Xie, J., Liu, S., Chen, S., Cao, X., Zhou, Y., et al. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04865-7 · Cited by 3
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Application of stem cells in the precise diagnosis and treatment of liver diseases
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A cell atlas of multiple liver organoids and the fetal liver based on scRNA-seq
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“…such as ll OPEN ACCESS cholangiocyte progenitor cells, can form three-dimensional structures in medium containing EGF, R-spondin 1 (RSPO1), FGF, HGF, and BMP. 11,12 This cultivation system can be used to produce two subtypes of organoids: bile duct organoids (BDOs) and human liver organoids (HLOs).”
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“Typically, LOs are generated in vitro by culturing mouse or human bile duct-derived bipotential facultative progenitor cells [7–9] or primary hepatocytes [7, 8, 10–12] within animal-derived matrices such as Matrigel.”
Organoid models: Regulations and prospects for the development of investigational new drugs
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“Hu et al [159] demonstrated the transplantation and regenerative ability of human hepatocyte organoids after implantation into mice, with extensive proliferation.”
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“For the maturation, G-heporgs were collected and transferred into maturation medium, which was composed of EM but without GA017, IGF2, CHIR99021 and with the addition of 20 ng/mL OSM and 200 nM dexamethasone (Dex, Sigma, D4902), supplemented with dispersing 5% growth factor reduced Matrigel and…”
InfluentialZhang, L., Zhao, J., Cheng, G., Wu, J., Liu, Y., Lei, G., & Wang, Q. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1753651 · Cited by 2
“However, the culture conditions for different types of organs vary greatly, making it challenging to standardize (13, 219, 220).”
González-Montero, M.-C., Criado, M., Alonso, M., Santos, N., Gutiérrez-Expósito, D., Giráldez, F. J., Balaña‐Fouce, R., Andrés, S., & García‐Estrada, C. (2026) · Frontiers in Veterinary Science · doi:10.3389/fvets.2026.1817725 · Cited by 2
Park, J. H., Lee, J., Park, S.-H., & Kim, K. (2021) · Organoid · doi:10.51335/organoid.2021.1.e7 · Cited by 2
“Accordingly, many studies have been conducted to produce organoids using stem cells, and human development and disease models have been reported for various tissues such as the small intestine, liver, and lungs [30,32-34].”
BackgroundThe application and research advances of organoids in clinical medicine
Mo, S., Guan, R., Long, Z., Cai, S., Peng, J., & GuoQiang, H. U. A. (2021) · Scientia Sinica Vitae · doi:10.1360/ssv-2021-0315 · Cited by 2
Contribution of the ELRs to the development of advanced in vitro models
Puertas‐Bartolomé, M., Venegas‐Bustos, D., Acosta, S., & Rodríguez‐Cabello, J. C. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1363865 · Cited by 2
Three-Dimensional Hepatocyte Spheroids: Model for Assessing Chemotherapy in Hepatocellular Carcinoma
Royo, F., Garcia‐Vallicrosa, C., Azparren‐Angulo, M., Bordanaba-Florit, G., López-Sarrio, S., & Falcón‐Pérez, J. M. (2024) · Biomedicines · doi:10.3390/biomedicines12061200 · Cited by 2
“Markers speci fi c to hepatocytes, such as ALB, HNF4A, and MRP4, can be assessed, along with some of the cytochromes for drug metabolization such as CYP3A4 (whose homolog in mice is CYP3A11) [15].”
BackgroundInfluentialOck, S. A., Kim, S.-Y., Kim, Y.-I., Lee, P., & Ju, W. S. (2024) · Organoid · doi:10.51335/organoid.2024.4.e9 · Cited by 2
“In contrast, HOs exhibit a notable 2–3-fold reduction in growth rate after 2 to 3 months, resulting in a lifespan that is approximately 3 times shorter than that of cholangiocyte organoids [4].”
BackgroundDevelopment of Novel 3D Spheroids for Discrete Subaortic Stenosis
Ji, P., Brimmer, S., Balaji, S., Birla, R. K., Heinle, J. S., Grande-Allen, J., & Keswani, S. G. (2024) · Cardiovascular Engineering and Technology · doi:10.1007/s13239-024-00746-x · Cited by 2
In toto biological framework: Modeling interconnectedness during human development
Yoneyama, Y., Wu, Y., Mori, K., & Takebe, T. (2025) · Developmental Cell · doi:10.1016/j.devcel.2024.09.027 · Cited by 2
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Modeling Metabolic Diseases with Organoids: A Review
Bustos, J., Alvarado-Gonzalez, J. C., de Abreu, D., Liebisch-Rey, H., Silva, A. R., Ortiz, D., Ramírez, L., Ortega, J. F. M., & Regalado, L. C. (2021) · Journal of Biomedical Research & Environmental Sciences · doi:10.37871/jbres1224 · Cited by 2
“It is one of the most popular methods for producing organoid and is relevant to this review as it has been used to generate both human and mouse hepatocyte organoids [11].”
Zhu, Y., Ding, Z., Wang, Y., Wu, Q., Chen, D., Wang, L., Li, Y., Yao, Y., Huang, J., Li, Y., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1239957 · Cited by 2
Baptista, P. M., & Penning, L. C. (2020) · Current Transplantation Reports · doi:10.1007/s40472-020-00266-2 · Cited by 2
Szkolnicka, D., & Hay, D. C. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818422-6.00040-x · Cited by 2
Elvassore, N., Urciuolo, A., Giobbe, G. G., Dong, Y., Michielin, F., Brandolino, L., Magnussen, M., Gagliano, O., Selmin, G., Scattolini, V., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-952864/v1 · Cited by 2
Self-citationDarmasaputra, G., Lopes, S. M. C. D. S., Clevers, H. C., & Galli, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.13.536716 · Cited by 4
Self-citationExpandable, Functional Hepatocytes Derived from Primary Cells Enable Liver TherapeuticsPreprint
Mallanna, S. K., Karanth, S. S., Marturano, J. E., Kudva, A. K., Lehmann, M., Morse, J. K., Jamiel, M., Norman, T. J., Wilson, C., Munarin, F., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.28.630269 · Cited by 2
Letourneur, D., Bergsten, E., Raynaud, N., Mondy, J., Nigro, G., Tsoumtsa, L. L., Vaysse, A., Descorps‐Declère, S., Yoshida, A. E., Stefani, C., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.02.680056 · Cited by 2
Proliferation/Differentiation in intestinal organoids as a balance of ligand-modulated EGFR trafficPreprint
Caracci, M. O., Seidler, S., Muñoz-Nava, L. M., Soetje, B., Michel, K., & Bastiaens, P. I. H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.30.715070 · Cited by 2
“Aberrant activity of EGF downstream signaling has been consistently associated with oncogenic transformations.”
Cryopreservation of Hepatocyte Organoid-Derived Cells Generated from Human iPS Cells
Nagai, W., Inui, J., Ueyama-Toba, Y., Asano, R., & Mizuguchi, H. (2025) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b25-00276 · Cited by 1
Recent advances in multicellular human liver models
Mun, S. J., Lee, J., Shin, Y., Eun, V., Ji, Y., & Son, M. J. (2022) · Organoid · doi:10.51335/organoid.2022.2.e26 · Cited by 1
“Liver organoids can be generated from adult tissue stem cells [9,60] and pluripotent stem cells (PSCs) [53,61].”
BackgroundCombination of untargeted and targeted proteomics for secretome analysis of L-WRN cells
Chen, Z., Leung, T. C. N., Lui, Y. L., Ngai, S. M., & Chung, H. Y. (2023) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-023-04534-9 · Cited by 1
“Importantly, the methodology developed in the current study can also be adapted to monitor the stability of other types of conditioned media, including Rspondin1conditioned medium [32], Wnt-conditioned medium [33], and noggin-conditioned medium [34], that contain individual target growth factors for culturing organoid…”
MethodCidonio, G., Brancato, V., Scognamiglio, C., Marzi, M., Barbetta, A., Riminucci, M., Nicassio, F., & Ruocco, G. (2023) · Tissue Engineering Part A · doi:10.1089/ten.tea.2023.29046.abstracts · Cited by 1
Physiological oxygen measurements in vitro-Schrödinger’s cat in 3D cell biology
Gottwald, E., Grün, C., Nies, C., & Liebsch, G. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1218957 · Cited by 1
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“19 Our team, directed by LH, has established a brand-new theory and culture system for the in vitro expansion of human hepatocytes and achieved a large-scale expansion of human primary hepatocytes in vitro, which can expand more than 10 000-fold in vitro.”
Intrasplenic Transplantation of Islets With a Platelet Shielding System Restores Glycemic Control
Song, L., Liu, C., Yang, A., Zhang, X., Wang, X., Teng, Y., Lü, D., Kuang, X., Wang, C., Zhang, J., et al. (2025) · Diabetes · doi:10.2337/db24-0856 · Cited by 1
Ji, Q., Tang, R., Liu, X., Yang, J., Liu, X., Li, Q., & Huang, R. (2025) · Biofabrication · doi:10.1088/1758-5090/aded37 · Cited by 3
Rashidi, H., Khalil, A., Froghi, S., Hall, A. R., Gélat, P., Davidson, B. R., Quaglia, A., & Saffari, N. (2025) · Cell Transplantation · doi:10.1177/09636897251342462 · Cited by 1
Wang, W.-L., Lian, H., Chen, Y. E., Song, Z., Tam, P. K. H., & Chen, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178387 · Cited by 1
“Hepatocyte organoid and cholangiocyte organoid growth were recorded, and experimental data were analyzed to assess organoid function and stability [49–51 The livers from four-week post-BDL male Balb/c mice were chosen ( n = 4).”
Arai, K., Fukuhara-Obonai, K., Ishimaru, S., Kojima, N., Mir, T. A., Kitsuka, T., & Hosaka, M. (2026) · Engineered Regeneration · doi:10.1016/j.engreg.2026.01.001 · Cited by 1
Lu, T., Ji, H., Li, Q., Zhang, J., Song, G., Wang, H., Zhu, C., Dong, C., & Shi, Y. Q. (2026) · Advanced Sensor and Energy Materials · doi:10.1016/j.asems.2026.100180 · Cited by 1
Multi-lineage hepatic organoids reveal toxic exosome mediated indirect hepatotoxicity
Sun, L., Zhang, Y., Niu, Y., Yang, H., Zhou, L., Jia, X., Chen, Y., Liu, Z., Wang, T., Liang, K., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-69548-0 · Cited by 1
“Hans Clevers ’ group demonstrated the long-term culture capability of adult stem cell organoids 23 , while Koike et al. constructed multi-organ organoids that modeled the liver, gallbladder, and pancreas 24 .”
Modeling age-related methylation changes in vitro with intestinal organoids
Vaidya, H., Calendo, G., Keith, K., Pompetti, A., Balch, C., Madžo, J., Jelı́nek, J., & Issa, J. J. (2026) · BMC Biology · doi:10.1186/s12915-026-02558-y · Cited by 1
An organoid model of the human adrenal cortex identifies drivers of steroidogenesis and zonation
Akkerman, N., Xu, Q., Valdeolivas, A., Okuda, R., Gaspa-Toneu, L., Cubela, I., Richardson, M., Giroud, N., Camp, J. G., & Beumer, J. (2026) · Cell Press Blue · doi:10.1016/j.cpblue.2026.100015 · Cited by 1
Zhao, X., Tao, X., Xiang, H., 孔欣, Zhang, X., Wu, Y. J., Guo, F., & Dong, D. (2026) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6c00013 · Cited by 1
Liver Organoids: From Disease Modelling to Regenerative Medicine
Wang, T., Qu, X., Si, J., Meng, J., Zhang, T., & Niu, S. (2026) · Cell Proliferation · doi:10.1111/cpr.70268 · Cited by 1
“Hu et al. showed that human liver cells transplanted into mice grew extensively after the cells were put into the mice, which is similar to how human liver cells behave when they are damaged [18].”
Nuciforo, S., Blukacz, L., Heusler, M.-A., Booij, T. H., Kübler, L., Trulsson, F., Boldanova, T., Wang, X., Ketterer, S., Matter, M. S., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117895 · Cited by 1
Application of Ex-Vivo/3D Organoid Models in COVID-19 Research
Basanthakumar, A. T. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.99100 · Cited by 1
Advances and applications in liver organoid technology
Lin, L., Miao, L. E. I., JiaMan, L. I. N., & Hu, W. (2021) · Scientia Sinica Vitae · doi:10.1360/ssv-2021-0283 · Cited by 1
Ethical Implications on Organoid
Yahaya, B. H., Shaffie, S. A. C., & Sasongko, T. H. (2022) · Stem cell biology and regenerative medicine · doi:10.1007/978-3-030-93056-1_10 · Cited by 1
Preparation of Functional Human Hepatocytes Ex Vivo
Okumura, A., & Tanimizu, N. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2557-6_20 · Cited by 1
Clinical Translation of Engineered Pulmonary Vascular Models
Yuan, Y. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-26625-6_14 · Cited by 1
Tumor Ecosystem-Mimicking Bioengineering Methods
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Organoids As a Tool to Fuel Basic Medical Research
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From parts to portal: Recapitulating hepatobiliary microarchitecture using multicellular organoids
Trampert, D. C. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.07.010 · Cited by 1
A 3D In Vitro Model of the Human Hepatobiliary Junction
Westerfield, A. D., Grzelak, K. A., Katsuyama, K., Kumar, V., Miller, B. M., Yun, J., Kirkpatrick, J. D., Mankus, D. V., Bisher, M. E., Lytton‐Jean, A. K. R., et al. (2026) · Advanced Science · doi:10.1002/advs.202514855 · Cited by 1
Bioengineering Liver Transplantation
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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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