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Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids
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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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Human assembloids recapitulate periportal liver tissue in vitro
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“Research groups have developed techniques that allow the in vitro production of primary human hepatocytes [30,31].”
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Zhang, J., Chen, X., Chai, Y., Zhuo, C., Xu, Y., Xue, T., Shao, D., Tao, Y., & Li, M. (2024) · Advanced Science · doi:10.1002/advs.202309899 · Cited by 25
Liver organoids: updates on generation strategies and biomedical applications
Liu, S., Cheng, C., Zhu, L., Zhao, T., Wang, Z., Yi, X., Yan, F., Wang, X., Li, C., Cui, T., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03865-3 · Cited by 29
“While the cholangiocyte organoids could potentially generate large quantities of hepatocytes in culture, these organoids of biliary origin appear to be recalcitrant in differentiating to hepatocytes in vitro or when engrafted into mice [22].”
BackgroundInfluentialGe, J.-Y., Wang, Y., Li, Q., Liu, F.-K., Lei, Q.-K., & Zheng, Y. (2024) · PeerJ · doi:10.7717/peerj.18422 · Cited by 26
Ethical challenges for pediatric liver organoid transplantation
Schneemann, S. A., Boers, S. N., van Delden, J. J. M., Nieuwenhuis, E. E. S., Fuchs, S. A., & Bredenoord, A. L. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aau8471 · Cited by 25
Roos, F. J. M., Verstegen, M. M. A., Albarinos, L. M., Roest, H. P., Poley, J., Tetteroo, G. W. M., IJzermans, J. N. M., & van der Laan, L. J. W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.630492 · Cited by 25
“Cholangiocytes organoids, either initiated from tissue or bile in both culture conditions, are most likely risen from primary cholangiocytes (Sampaziotis et al., 2017; Hu et al., 2018; Aloia et al., 2019; Planas-Paz et al., 2019).”
BackgroundMazari‐Arrighi, E., Ayollo, D., Farhat, W., Marret, A., Gontran, E., Dupuis‐Williams, P., Larghero, J., Chatelain, F., & Fuchs, A. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.121207 · Cited by 24
Optimized 3D Culture of Hepatic Cells for Liver Organoid Metabolic Assays
Gamboa, C. M., Wang, Y., Xu, H., Kalemba, K. M., Wondisford, F. E., & Sabaawy, H. E. (2021) · Cells · doi:10.3390/cells10123280 · Cited by 27
3D imaging for driving cancer discovery
van Ineveld, R. L., van Vliet, E. J., Wehrens, E. J., Alieva, M., & Rios, A. C. (2022) · The EMBO Journal · doi:10.15252/embj.2021109675 · Cited by 27
“Such fixed organoid 3D imaging has been widely applied to organoids of various species and tissue origin (Hu et al , 2018; Schutgens et al , 2019; Dekkers et al , 2020; Post et al , 2020), as well as disease states.”
Self-citationThe Potential Clinical Use of Stem/Progenitor Cells and Organoids in Liver Diseases
Nikokiraki, C., Psaraki, A., & Roubelakis, M. G. (2022) · Cells · doi:10.3390/cells11091410 · Cited by 29
Cuvellier, M., Rose, S., Ezan, F., Jarry, U., Oliveira, H., Bruyère, A., Rochelle, C. D. L., Legagneux, V., Langouët, S., & Baffet, G. (2022) · Biofabrication · doi:10.1088/1758-5090/ac7825 · Cited by 25
“In parallel, 3D cell culture models of PHH embedded in matrix such as including alginate [13], Matrigel [14–16], or collagen [9, 17, 18] have been widely developed and optimized in the last decade to more accurately reflect in vivo physiology and enable the maintenance of tissue specific functions.”
Cell transplantation-based regenerative medicine in liver diseases
Cardinale, V., Lanthier, N., Baptista, P. M., Carpino, G., Carnevale, G., Orlando, G., Angelico, R., Manzia, T. M., Schuppan, D., Pinzani, M., et al. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.06.005 · Cited by 27
“Indeed, use of human adult hepatocytederived organoids is controversial because current protocols mainly work with fetal specimens (Hu et al., 2018).”
BackgroundInfluentialLiver organoids: Current advances and future applications for hepatology
Kim, Y., Kang, M., Mamo, M. G., Adisasmita, M., Huch, M., & Choi, D. (2025) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.1040 · Cited by 26
The Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery
Bae, J., Choi, Y. S., Cho, G., & Jang, S. J. (2022) · Cancers · doi:10.3390/cancers14092144 · Cited by 27
Organoids for Liver Stage Malaria Research
Mellin, R., & Boddey, J. A. (2019) · Trends in Parasitology · doi:10.1016/j.pt.2019.12.003 · Cited by 28
Pek, N. M. Q., Liu, K. J., Nichane, M., & Ang, L. T. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.09.016 · Cited by 25
Collett, S., Torresi, J., Silveira, L. E., Truong, V. K., Christiansen, D., Tran, B. M., Vincan, E., Ramsland, P. A., & Elbourne, A. J. (2021) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2021.02.067 · Cited by 24
Foster, N. C., Hall, N. M., & Haj, A. J. E. (2021) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2020.0354 · Cited by 24
“104,105 There are well-described organoid models for tissues such as brain, 106 stomach, 107 and liver, 108 which fulfil all of these criteria.”
3D cell culture model: From ground experiment to microgravity study
Ma, C., Duan, X., & Lei, X. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1136583 · Cited by 27
“In this system, single hepatocytes can create organoids that can be cultivated for several months while keeping important morphological, functional, and gene expression characteristics (Hu et al., 2018).”
BackgroundChen, Y., Liu, Y., Chen, S., Zhang, L., Rao, J., Lu, X., & Ma, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1180184 · Cited by 24
Li, F., Wei, H., Jin, Y., Xue, T., Xu, Y., Wang, H., Ju, E., Tao, Y., & Li, M. (2023) · ACS Nano · doi:10.1021/acsnano.3c08495 · Cited by 23
Bioartificial livers: a review of their design and manufacture
Tuerxun, K., He, J., Ibrahim, I., Yusupu, Z., Yasheng, A., Xu, Q., Tang, R., Aikebaier, A., Wu, Y., Tuerdi, M., et al. (2022) · Biofabrication · doi:10.1088/1758-5090/ac6e86 · Cited by 24
“Additionally, three-dimensional (3D) organoid culture has proven to be an effective method for the long-term culturing of primary hepatocytes [40].”
Human liver organoids for disease modeling of fibrolamellar carcinoma
Narayan, N. J. C., Requena, D., Lalazar, G., Ramos-Espiritu, L. S., Ng, D., Levin, S., Shebl, B., Wang, R., Hammond, W. J., Saltsman, J. A., et al. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.06.003 · Cited by 25
“conditioned media were made in-house (Broutier et al., 2017; Hu et al., 2018; Huch et al., 2015).”
BackgroundMethodInfluentialSelf-citationYoon, Y., Gong, S. C., Kim, M. Y., Baik, S. K., Hong, J.-E., Rhee, K., Ryu, H., & Eom, Y. W. (2023) · Cells · doi:10.3390/cells12212514 · Cited by 26
“Recently, human and mouse hepatocytes were cultured long term as organoids and successfully engrafted in damaged mouse livers [19].”
BackgroundBioengineered Tubular Biliary Organoids
Elci, B. S., Nikolaev, M., Rezakhani, S., & Lütolf, M. P. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202302912 · Cited by 23
Cholangiocarcinoma Disease Modelling Through Patients Derived Organoids
Amato, F., Rae, C. J., Prete, M. G., & Braconi, C. (2020) · Cells · doi:10.3390/cells9040832 · Cited by 23
Oxytocin promotes hepatic regeneration in elderly mice
Luo, D., Jin, B., Zhai, X., Li, J., Liu, C., Guo, W., & Li, J. (2021) · iScience · doi:10.1016/j.isci.2021.102125 · Cited by 24
Muhr, J., & Hagey, D. W. (2021) · BioEssays · doi:10.1002/bies.202000285 · Cited by 23
“[27] This has even been found to involve the transdifferentiation of one cell type into another, and thus illustrates the complex interplay between differentiation, proliferation and cell fate decisions.[28]”
BackgroundSignalling pathways and transcriptional regulators orchestrating liver development and cancer
Campbell, S. A., Stephan, T. L., Lotto, J., Cullum, R., Drissler, S., & Hoodless, P. A. (2021) · Development · doi:10.1242/dev.199814 · Cited by 22
Zhang, W., Lu, J., Feng, L., Xue, H., Shen, S., Lai, S., Li, P., Li, P., Kuang, J., Yang, Z., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45520-8 · Cited by 22
“Asdescribedpreviously 81 ,isolatedlivercellsof Hsp90 β fl / fl or Hsp90 β Δ Hep mice were counted and mixed with Matrigel in suspension plates (Greiner).”
Li, Y., Chen, J., Liang, J., Zhang, Y., Wang, Q., Ren, X., Wei, J., Gong, Q.-C., Zhang, J., Jiang, N., et al. (2021) · Protein & Cell · doi:10.1007/s13238-021-00893-0 · Cited by 22
“Based on the recently reported growth-factor-maintained fetal liver organoid culture system (Hu et al., 2018; Prior et al., 2019), we cultivated human fetal liver organoids using 8–12 weeks post-coitum (W) human liver cell clusters.”
MethodAdvancements in MAFLD Modeling with Human Cell and Organoid Models
Wang, S.-X., Yan, J.-S., & Chan, Y.-S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911850 · Cited by 22
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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