Large‐Scale Production of LGR5‐Positive Bipotential Human Liver Stem Cells
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Background and Aims: The gap between patients on transplant waiting lists and available donor organs is steadily increasing. Human organoids derived from leucine‐rich repeat‐containing G protein‐coupled receptor 5 (LGR5)–positive adult stem cells represent an exciting new cell source for liver regeneration; however, culturing large numbers of organoids with current protocols is tedious and the level of hepatic differentiation is limited. Approach and Results: Here, we established a method for the expansion of large quantities of human liver organoids in spinner flasks. Due to improved oxygenation in the spinner flasks, organoids rapidly proliferated and reached an average 40‐fold cell expansion after 2 weeks, compared with 6‐fold expansion in static cultures. The organoids repopulated decellularized liver discs and formed liver‐like tissue. After differentiation in spinner flasks, mature hepatocyte markers were highly up‐regulated compared with static organoid cultures, and cytochrome p450 activity reached levels equivalent to hepatocytes. Conclusions: We established a highly efficient method for culturing large numbers of LGR5‐positive stem cells in the form of organoids, which paves the way for the application of organoids for tissue engineering and liver transplantation.
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Liver organoids derived from LGR5-positive liver progenitor cells can be stably maintained for months and can differentiate into functionally competent hepatocytes and cholangiocytes.
“Liver organoids derived from leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5)–positive liver progenitor cells (LPC) can be stably maintained for months and can differentiate into functionally competent hepatocytes and cholangiocytes [14–16].”
From High-throughput human microfluidic organoid-on-a-chip platform for modeling liver diseases and screening nanotherapeutics. (2026) · cites this paper as [15]
The introductory passage says LGR5-positive liver organoids can be expanded for years, while the Discussion reports that this paper's spinner-flask organoids were maintained for at least six weeks. The Results show differentiation toward cholangiocyte-like and hepatocyte-like cells and assays of hepatocyte function, but not functional competence of cholangiocytes. The Discussion also cautions that the hepatocyte-like cells did not reach a fully mature phenotype. (LLM, conf=0.86)
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Cites
Generation of cerebral organoids from human pluripotent stem cells
Lancaster, M. A., & Knoblich, J. A. (2014) · Nature Protocols · doi:10.1038/nprot.2014.158 · Cited by 1,764 · 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
Self-citationIn vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration
Huch, M., Dorrell, C., Boj, S. F., van Es, J. H., Li, V. S. W., van de Wetering, M., Sato, T., Hamer, K., Sasaki, N., Finegold, M. J., et al. (2013) · Nature · doi:10.1038/nature11826 · Cited by 1,555 · see citing works
Self-citationHuman primary liver cancer–derived organoid cultures for disease modeling and drug screening
Broutier, L., Mastrogiovanni, G., Verstegen, M. M., Francies, H. E., Gavarró, L. M., Bradshaw, C. R., Allen, G. E., Arnes-Benito, R., Sidorova, O., Gaspersz, M. P., et al. (2017) · Nature Medicine · doi:10.1038/nm.4438 · Cited by 1,471 · cited 1× · see citing works
“As a positive control, human tumoroid liver organoids derived from a cholangiocarcinoma of a 76-year old female donor were used.(33) Visible tumors developed in approximately 8 weeks (tumoroid liver organoids), at which point the mice were euthanized and skin tissues were harvested to assess the growth and histology o…”
MethodSelf-citationDesigner matrices for intestinal stem cell and organoid culture
Gjorevski, N., Sachs, N., Manfrin, A., Giger, S., Bragina, M. E., Ordóñez-Morán, P., Clevers, H., & Lutolf, M. P. (2016) · Nature · doi:10.1038/nature20168 · Cited by 1,426 · see citing works
Self-citationAn estimation of the number of cells in the human body
Bianconi, E., Piovesan, A., Facchin, F., Beraudi, A., Casadei, R., Frabetti, F., Vitale, L., Pelleri, M. C., Tassani, S., Piva, F., et al. (2013) · Annals of Human Biology · doi:10.3109/03014460.2013.807878 · Cited by 1,012 · see citing works
Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids
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., et al. (2018) · Cell · doi:10.1016/j.cell.2018.11.013 · Cited by 837 · see citing works
Self-citationThe use of whole organ decellularization for the generation of a vascularized liver organoid
Baptista, P. M., Siddiqui, M. M., Lozier, G., Rodriguez, S. R., Atala, A., & Soker, S. (2011) · Hepatology · doi:10.1002/hep.24067 · Cited by 681 · see citing works
Self-citationGeneration of Functional Human Hepatic Endoderm From Human Induced Pluripotent Stem Cells
Sullivan, G. J., Hay, D. C., Park, I.-H., Fletcher, J., Hannoun, Z., Payne, C. M., Dalgetty, D., Black, J. R., Ross, J. A., Samuel, K., et al. (2010) · Hepatology · doi:10.1002/hep.23335 · Cited by 445 · see citing works
Hay, D. C., Zhao, D., Fletcher, J., Hewitt, Z. A., McLean, D., Urruticoechea-Uriguen, A., Black, J. R., Elcombe, C., Ross, J. A., Wolf, R., et al. (2008) · Stem Cells · doi:10.1634/stemcells.2007-0718 · Cited by 441 · see citing works
The hope and the hype of organoid research
Huch, M., Knoblich, J. A., Lutolf, M. P., & Martinez-Arias, A. (2017) · Development · doi:10.1242/dev.150201 · Cited by 409 · cited 1× · see citing works
“(9,10) Unfortunately, reproducibility and upscaling of current organoid systems remain major bottlenecks in their clinical application.(11) Establishing large numbers of organoids with current protocols is tedious, as organoids are cultured in droplets of Matrigel,(9,10) which hampers clinically relevant production ti…”
BackgroundHuman hepatocyte transplantation: current experience and future challenges
Dhawan, A., Puppi, J., Hughes, R. D., & Mitry, R. R. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.44 · Cited by 362 · see citing works
Baxter, M. A., Withey, S., Harrison, S. P., Segeritz, C., Zhang, F., Atkinson-Dell, R., Rowe, C., Gerrard, D. T., Sison-Young, R. L. C., Jenkins, R., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.10.016 · Cited by 353 · see citing works
Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture
Peng, W. C., Logan, C. Y., Fish, M., Anbarchian, T., Aguisanda, F., Álvarez-Varela, A., Wu, P., Jin, Y., Zhu, J., Li, B., et al. (2018) · Cell · doi:10.1016/j.cell.2018.11.012 · Cited by 331 · see citing works
A Whole-Organ Regenerative Medicine Approach for Liver Replacement
Soto-Gutierrez, A., Zhang, L., Medberry, C., Fukumitsu, K., Faulk, D., Jiang, H., Reing, J., Gramignoli, R., Komori, J., Ross, M., et al. (2011) · Tissue Engineering Part C: Methods · doi:10.1089/ten.tec.2010.0698 · Cited by 311 · see citing works
In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity
Zhang, K., Zhang, L., Liu, W., Ma, X., Cen, J., Sun, Z., Wang, C., Feng, S., Zhang, Z., Yue, L., et al. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.10.018 · Cited by 252 · cited 1× · see citing works
“Interestingly, during the writing of this manuscript, culture conditions for the in vitro expansion of primary human hepatocytes in 2D(28) and primary mouse and human fetal hepatocytes as 3D organoids(29,30) have been established.”
BackgroundBioreactor development for stem cell expansion and controlled differentiation
King, J. A., & Miller, W. M. (2007) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2007.05.034 · Cited by 247 · see citing works
Wang, Y., Cui, C.-B., Yamauchi, M., Miguez, P., Roach, M., Malavarca, R., Costello, J. M., Cardinale, V., Wauthier, E., Barbier, C., et al. (2011) · Hepatology · doi:10.1002/hep.24012 · Cited by 220 · see citing works
Regenerative medicine strategies
Atala, A. (2012) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2011.10.013 · Cited by 173 · see citing works
Self‐assembled liver organoids recapitulate hepatobiliary organogenesis in vitro
Vyas, D., Baptista, P. M., Brovold, M., Moran, E. C., Gaston, B., Booth, C., Samuel, M., Atala, A., & Söker, S. (2017) · Hepatology · doi:10.1002/hep.29483 · Cited by 134 · see citing works
Self-citationFraczek, J., Bolleyn, J., Vanhaecke, T., Rogiers, V., & Vinken, M. (2013) · Archives of Toxicology · doi:10.1007/s00204-012-0983-3 · Cited by 119 · see citing works
Technological Overview of iPS Induction from Human Adult Somatic Cells
Bayart, É., & Cohen‐Haguenauer, O. (2013) · Current Gene Therapy · doi:10.2174/1566523211313020002 · Cited by 112 · see citing works
Bioreactor design for clinical‐grade expansion of stem cells
dos Santos, F., Andrade, P. Z., da Silva, C. L., & Cabral, J. M. S. (2013) · Biotechnology Journal · doi:10.1002/biot.201200373 · Cited by 106 · see citing works
Biotechnology Challenges to In Vitro Maturation of Hepatic Stem Cells
Chen, C., Soto–Gutiérrez, A., Baptista, P. M., & Spee, B. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.01.066 · Cited by 103 · see citing works
Self-citationKumaran, V., Joseph, B., Benten, D., & Gupta, S. K. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.08.006 · Cited by 69 · see citing works
Massai, D., Isu, G., Madeddu, D., Cerino, G., Falco, A., Frati, C., Gallo, D., Deriu, M. A., Labate, G. F. D., Quaini, F., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0154610 · Cited by 62 · see citing works
From organoids to organs: Bioengineering liver grafts from hepatic stem cells and matrix
Willemse, J., Lieshout, R., van der Laan, L. J. W., & Verstegen, M. M. A. (2017) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2017.03.003 · Cited by 44 · see citing works
Self-citationChen, C., Plá-Palacín, I., Baptista, P. M., Shang, P., Oosterhoff, L. A., van Wolferen, M. E., Penning, L. C., Geijsen, N., & Spee, B. (2018) · Biotechnology and Bioengineering · doi:10.1002/bit.26784 · Cited by 19 · see citing works
Self-citationAssessment of in Vitro Applicability of Reversibly Immortalized NKNT-3 Cells and Clonal Derivatives
Hoekstra, R., Deurholt, T., ten Bloemendaal, L., Desille, M., van Wijk, A. C. W. A., Clément, B., Elferink, R. P. J. O., van Gulik, T. M., & Chamuleau, R. A. F. M. (2006) · Cell Transplantation · doi:10.3727/000000006783981873 · Cited by 19 · see citing works
Self-citationKheolamai, P., & Dickson, A. J. (2009) · BMC Molecular Biology · doi:10.1186/1471-2199-10-35 · Cited by 17 · see citing works
Adam, A. A. A., van der Mark, V. A., Donkers, J. M., Wildenberg, M. E., Elferink, R. P. J. O., Chamuleau, R. A. F. M., & Hoekstra, R. (2018) · PLoS ONE · doi:10.1371/journal.pone.0193664 · Cited by 14 · see citing works
Self-citationThe versatile and plastic liver
Huch, M. (2015) · Nature · doi:10.1038/517155a · Cited by 12 · see citing works
Organoid cultures boost human liver cell expansion
Forbes, S. J. (2015) · Hepatology · doi:10.1002/hep.27970 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Polystyrene microplastics induce hepatotoxicity and disrupt lipid metabolism in the liver organoids
Cheng, W., Li, X., Zhou, Y., Yu, H., Xie, Y., Guo, H., Wang, H., Li, Y., Feng, Y., & Wang, Y. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.150328 · Cited by 317 · 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-citationBernal, P. N., Bouwmeester, M., Madrid-Wolff, J. A., Falandt, M., Florczak, S., Rodriguez, N. G., Li, Y., Größbacher, G., Samsom, R., van Wolferen, M. E., et al. (2022) · Advanced Materials · doi:10.1002/adma.202110054 · Cited by 290 · see citing works
Self-citationClinical applications of human organoids
Verstegen, M. M. A., Coppes, R. P., Béghin, A., Coppi, P. D., Gerli, M., de Graeff, N., Pan, Q., Saito, Y., Shi, S., ZADPOOR, A. A., et al. (2025) · Nature Medicine · doi:10.1038/s41591-024-03489-3 · Cited by 228 · see citing works
Self-citationA Chemically Defined Hydrogel for Human Liver Organoid Culture
Ye, S., Boeter, J. W. B., Mihajlovic, M., van Steenbeek, F. G., van Wolferen, M. E., Oosterhoff, L. A., Marsee, A., Caiazzo, M., van der Laan, L. J. W., Penning, L. C., et al. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202000893 · Cited by 165 · see citing works
Self-citationRadiation‐induced tissue damage and response
McBride, W. H., & Schaue, D. (2020) · The Journal of Pathology · doi:10.1002/path.5389 · Cited by 155 · see citing works
A critical perspective on 3D liver models for drug metabolism and toxicology studies
Serras, A. S., Rodrigues, J. S., Cipriano, M., Rodrigues, A. V., Oliveira, N. G., & Miranda, J. P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.626805 · Cited by 138 · see citing works
Zhou, Y., Wu, Q., Li, Y., Feng, Y., Wang, Y., & Cheng, W. (2023) · Environment International · doi:10.1016/j.envint.2023.108171 · Cited by 138 · see citing works
Scalable production of tissue-like vascularized liver organoids from human PSCs
Harrison, S. P., Siller, R., Tanaka, Y., Chollet, M. E., de la Morena-Barrio, M. E., Xiang, Y., Patterson, B., Andersen, E., Bravo-Pérez, C., Kempf, H., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01074-1 · Cited by 119 · see citing works
Liver organoid as a 3D in vitro model for drug validation and toxicity assessment
Brooks, A., Liang, X., Zhang, Y., Zhao, C., Roberts, M. S., Wang, H., Zhang, L., & Crawford, D. H. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105608 · Cited by 108 · see citing works
Willemse, J., van Tienderen, G., van Hengel, E., Schurink, I., van der Ven, D., Kan, Y., de Ruiter, P., Rosmark, O., Westergren-Thorsson G, G., Schneeberger, K., et al. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121473 · Cited by 106 · see citing works
Self-citationNguyen, V. V. T., Ye, S., Gkouzioti, V., van Wolferen, M. E., Yengej, F. Y., Melkert, D., Siti, S., de Jong, B., Besseling, P. J., Spee, B., et al. (2022) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12280 · Cited by 105 · see citing works
Self-citationKidney Organoids and Tubuloids
Yengej, F. A. Y., Jansen, J., Rookmaaker, M. B., Verhaar, M. C., & Clevers, H. C. (2020) · Cells · doi:10.3390/cells9061326 · Cited by 100 · see citing works
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Licata, J. P., Schwab, K. H., Har-el, Y.-E., Gerstenhaber, J. A., & Lelkes, P. I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411427 · Cited by 99 · see citing works
Verstegen, M. M. A., Roos, F. J. M., Burka, K., Gehart, H., Jager, M., de Wolf, M., Bijvelds, M. J. C., de Jonge, H. R., Ardisasmita, A. I., van Huizen, N. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-79082-8 · Cited by 86 · see citing works
Self-citationCheng, W., Zhou, Y., Xie, Y., Li, Y., Zhou, R., Wang, H., Feng, Y., & Wang, Y. (2023) · Science of The Total Environment · doi:10.1016/j.scitotenv.2022.158585 · Cited by 85 · see citing works
Li, P., Li, Y., Wang, Y., Liu, J., Lavrijsen, M., Li, Y., Zhang, R., Verstegen, M. M. A., Wang, Y., Li, T., et al. (2022) · Science Advances · doi:10.1126/sciadv.abj5908 · Cited by 82 · see citing works
Self-citationConstruction of tumor organoids and their application to cancer research and therapy
Lv, J., Du, X., Wang, M., Su, J., Wei, Y., & Xu, C. (2024) · Theranostics · doi:10.7150/thno.91362 · Cited by 86 · see citing works
De novo neo-hyaline-cartilage from bovine organoids in viscoelastic hydrogels
Crispim, J. F., & Ito, K. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.04.008 · Cited by 71 · see citing works
In Vitro Models for the Study of Liver Biology and Diseases: Advances and Limitations
Kaur, S., Kidambi, S., Ortega‐Ribera, M., Thủy, L. T. T., Nieto, N., Cogger, V. C., Xie, W., Tacke, F., & Gracia‐Sancho, J. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.11.008 · Cited by 67 · see citing works
Human liver organoids: From generation to applications
Afonso, M. B., Marques, V., van Mil, S. W. C., & Rodrigues, C. M. P. (2024) · Hepatology · doi:10.1097/hep.0000000000000343 · Cited by 61 · see citing works
Shiota, J., Samuelson, L. C., & Razumilava, N. (2021) · Hepatology · doi:10.1002/hep.31772 · Cited by 57 · see citing works
Progress in human liver organoids
Sun, L., & Hui, L. (2020) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjaa013 · Cited by 55 · see citing works
Liver Organoids: Formation Strategies and Biomedical Applications
Zhu, X., Zhang, B., He, Y., & Bao, J. (2021) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-021-00357-w · Cited by 55 · see citing works
Fluid flow to mimic organ function in 3D in vitro models
Juste-Lanas, Y., Hervás-Raluy, S., García‐Aznar, J. M., & González‐Loyola, A. (2023) · APL Bioengineering · doi:10.1063/5.0146000 · Cited by 50 · see citing works
Reconstructing the tumor architecture into organoids
Luo, Z., Zhou, X., Mandal, K., He, N., Wennerberg, W., Qu, M., Jiang, X., Sun, W., & Khademhosseini, A. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113839 · Cited by 49 · see citing works
Bioprinting of Human Liver‐Derived Epithelial Organoids for Toxicity Studies
Bouwmeester, M., Bernal, P. N., Oosterhoff, L. A., van Wolferen, M. E., Lehmann, V., Vermaas, M., Buchholz, M., Peiffer, Q. C., Malda, J., van der Laan, L. J. W., et al. (2021) · Macromolecular Bioscience · doi:10.1002/mabi.202100327 · Cited by 49 · see citing works
Self-citationGarcia, A. L. C., Arlt, V. M., & Phillips, D. H. (2021) · Mutagenesis · doi:10.1093/mutage/geab023 · Cited by 45 · see citing works
Organoids in the oral and maxillofacial region: present and future
Wu, Y., Li, X., Liu, H., Yang, X. Y., Li, R., Zhao, H., & Shang, Z. (2024) · International Journal of Oral Science · doi:10.1038/s41368-024-00324-w · Cited by 49 · see citing works
van Berlo, D., van de Steeg, E., Amirabadi, H. E., & Masereeuw, R. (2021) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2021.05.001 · Cited by 43 · see citing works
Advancements in stem cell-derived hepatocyte-like cell models for hepatotoxicity testing
Jin, M., Xiao, Y., Liao, W., Chen, Q., Yang, W., Li, Y., Li, S., Gao, Y., Peng, Q., & Zhou, S. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02152-9 · Cited by 41 · see citing works
Roos, F. J. M., Wu, H., Willemse, J., Lieshout, R., Albarinos, L. A. M., Kan, Y., Poley, J., Bruno, M. J., de Jonge, J., Bártfai, R., et al. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.566 · Cited by 40 · see citing works
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Reza, H. A., Okabe, R., & Takebe, T. (2021) · Transplant International · doi:10.1111/tri.14128 · Cited by 39 · see citing works
Shrestha, S., Lekkala, V. K. R., Acharya, P., Kang, S., Vanga, M. G., & Lee, M. (2024) · Lab on a Chip · doi:10.1039/d4lc00149d · Cited by 38 · see citing works
Shi, S., Verstegen, M. M. A., Roest, H. P., Ardisasmita, A. I., Cao, W., Roos, F. J. M., de Ruiter, P. E., Niemeijer, M., Pan, Q., IJzermans, J. N. M., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.10.009 · Cited by 38 · see citing works
Self-citationArdisasmita, A. I., Schene, I. F., Joore, I. P., Kok, G., Hendriks, D. F. G., Artegiani, B., Mokrý, M., Nieuwenhuis, E. E. S., & Fuchs, S. A. (2022) · Communications Biology · doi:10.1038/s42003-022-04046-9 · Cited by 37 · see citing works
Self-citationWillemse, J., Roos, F. J. M., Voogt, I. J., Schurink, I. J., Bijvelds, M., de Jonge, H. R., van der Laan, L. J. W., de Jonge, J., & Verstegen, M. M. A. (2021) · Biotechnology and Bioengineering · doi:10.1002/bit.27613 · Cited by 35 · see citing works
Self-citationKim, D., Youn, J., Kim, J., Lee, J., Yoon, J., & Kim, D. S. (2026) · npj Biomedical Innovations. · doi:10.1038/s44385-025-00054-6 · Cited by 39 · see citing works
Hallmarks of the human intestinal microbiome on liver maturation and function
Almeida, J. I., Tenreiro, M. F., Martínez‐Santamaría, L., Guerrero‐Aspizua, S., Gisbert, J. P., Alves, P. M., Serra, M., & Baptista, P. M. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.10.015 · Cited by 37 · see citing works
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Hu, Y., Hu, X., Luo, J. C., Huang, J., Sun, Y., Li, H., Qiao, Y., Wu, H., Li, J., Zhou, L., et al. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01136-x · Cited by 33 · see citing works
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Zhang, Y., Li, L., Dong, L., Cheng, Y., Huang, X., Xue, B., Jiang, C., Cao, Y., & Yang, J. (2024) · Chem & Bio Engineering · doi:10.1021/cbe.4c00079 · Cited by 30 · see citing works
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Bouwmeester, M., Tao, Y., Proença, S., van Steenbeek, F. G., Samsom, R., Nijmeijer, S. M., Sinnige, T. L., van der Laan, L. J. W., Legler, J., Schneeberger, K., et al. (2023) · Molecules · doi:10.3390/molecules28020621 · Cited by 30 · see citing works
Self-citationPadma, A. M., Carrière, L., Karlsson, F. K., Sehiç, E., Bandstein, S., Tiemann, T. T., Oltean, M., Song, M. J., Brännström, M., & Hellström, M. (2021) · npj Regenerative Medicine · doi:10.1038/s41536-021-00136-0 · Cited by 29 · see citing works
Zhang, J., Xu, Y., Zhuo, C., Shi, R., Wang, H., Hu, Z., Chan, H. F., Kim, H., Tao, Y., & Li, M. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122014 · Cited by 29 · see citing works
Ma, Q., Tao, H., Li, Q., Zhai, Z., Zhang, X., Lin, Z., Kuang, N., & Pan, J. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac942 · Cited by 27 · see citing works
The promise of human organoids in the digestive system
Funata, M., Nio, Y., Erion, D. M., Thompson, W. L., & Takebe, T. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-00661-3 · Cited by 27 · see citing works
Human Cholangiocytes Form a Polarized and Functional Bile Duct on Hollow Fiber Membranes
Wang, Z., Faria, J., van der Laan, L. J. W., Penning, L. C., Masereeuw, R., & Spee, B. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.868857 · Cited by 27 · see citing works
Self-citationLiver Organoids: Updates on Disease Modeling and Biomedical Applications
Caiazza, C., Parisi, S., & Caiazzo, M. (2021) · Biology · doi:10.3390/biology10090835 · Cited by 27 · see citing works
Willemse, J., van der Laan, L. J. W., de Jonge, J., & Verstegen, M. M. A. (2022) · Bioengineering · doi:10.3390/bioengineering9030110 · Cited by 26 · see citing works
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 · see citing works
Abbasalizadeh, S., Babaee, S., Kowsari‐Esfahan, R., Mazidi, Z., Shi, Y., Wainer, J. A., Cabral, J. M. S., Langer, R., Traverso, G., & Baharvand, H. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202210233 · Cited by 27 · see citing works
Lekkala, V. K. R., Kang, S.-Y., Liu, J., Shrestha, S., Acharya, P., Joshi, P., Zolfaghar, M., Lee, M., Vanga, M. G., Jamdagneya, P., et al. (2024) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.4c00179 · Cited by 25 · see citing works
Ge, J.-Y., Wang, Y., Li, Q., Liu, F.-K., Lei, Q.-K., & Zheng, Y. (2024) · PeerJ · doi:10.7717/peerj.18422 · Cited by 25 · see citing works
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 26 · see citing works
Self-citationPaola, F. J. D., Calafato, G., Piccaluga, P. P., Tallini, G., & Rhoden, K. J. (2025) · Journal of Personalized Medicine · doi:10.3390/jpm15080394 · Cited by 24 · see citing works
Liver ductal organoids reconstruct intrahepatic biliary trees in decellularized liver grafts
Tomofuji, K., Fukumitsu, K., Kondo, J., Horie, H., Makino, K., Wakama, S., Ito, T., Oshima, Y., Ogiso, S., Ishii, T., et al. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121614 · Cited by 24 · see citing works
Hoogduijn, M. J., Montserrat, N., van der Laan, L. J. W., Dazzi, F., Perico, N., Kastrup, J., Gilbo, N., Ploeg, R. J., Roobrouck, V. D., Casiraghi, F., et al. (2020) · Transplant International · doi:10.1111/tri.13608 · Cited by 25 · see citing works
Hepatic bile acid synthesis and secretion: Comparison of in vitro methods
de Bruijn, V. M. P., Wang, Z., Bakker, W., Zheng, W., Spee, B., & Bouwmeester, H. (2022) · Toxicology Letters · doi:10.1016/j.toxlet.2022.06.004 · Cited by 22 · see citing works
Self-citationRegenerative medicine technologies applied to transplant medicine. An update
Petrosyan, A., Montali, F., Peloso, A., Citro, A., Byers, L. N., Pointe, C. L., Suleiman, M., Marchetti, A., McNeill, E. P., Speer, A. L., et al. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.1015628 · Cited by 21 · see citing works
Liver Organoids, Novel and Promising Modalities for Exploring and Repairing Liver Injury
He, C., Lu, D., Lin, Z., Chen, H. H., Li, H., Yang, X., Yang, M., Wang, K., Wei, X., Zheng, S., et al. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10456-3 · Cited by 21 · see citing works
Toprakhisar, B., Verfaillie, C. M., & Kumar, M. (2023) · Cells · doi:10.3390/cells12020301 · Cited by 24 · see citing works
Microfabricated disk technology: Rapid scale up in midbrain organoid generation
Mohamed, N., Lépine, P., Lacalle‐Aurioles, M., Sirois, J., Mathur, M., Reintsch, W., Beitel, L. K., Fon, E. A., & Durcan, T. M. (2021) · Methods · doi:10.1016/j.ymeth.2021.07.008 · Cited by 22 · see citing works
Cao, D., Ge, J.-Y., Wang, Y., Oda, T., & Zheng, Y. (2021) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i29.4784 · Cited by 19 · see citing works
Gehling, K., Parekh, S., Schneider, F., Kirchner, M., Kondylis, V., Nikopoulou, C., & Tessarz, P. (2022) · Life Science Alliance · doi:10.26508/lsa.202101340 · Cited by 20 · see citing works
Gerardo‐Nava, J., Jansen, J., Günther, D., Klasen, L., Thiebes, A. L., Nießing, B., Bergerbit, C., Meyer, A. A., Linkhorst, J., Barth, M., et al. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202301030 · Cited by 18 · see citing works
van Tienderen, G. S., Willemse, J., van Loo, B., van Hengel, E. V. A., de Jonge, J., van der Laan, L. J. W., Leijten, J., & Verstegen, M. M. A. (2022) · Cells · doi:10.3390/cells11223657 · Cited by 17 · see citing works
Self-citationCellular Architects at Work: Cells Building their Own Microgel Houses
Bulut, S., Günther, D., Bund, M., Haats, C., Bissing, T., Bastard, C., Weßling, M., Laporte, L. D., & Pich, A. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202302957 · Cited by 17 · see citing works
Human Hepatobiliary Organoids: Recent Advances in Drug Toxicity Verification and Drug Screening
Fang, H., Xu, H., Yu, J., Cao, H., & Li, L. (2024) · Biomolecules · doi:10.3390/biom14070794 · Cited by 16 · see citing works
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 15 · see citing works
Tumor Organoids as a Research Tool: How to Exploit Them
Booij, T. H., Cattaneo, C. M., & Hirt, C. (2022) · Cells · doi:10.3390/cells11213440 · Cited by 16 · see citing works
Jabri, A., Khan, J. A., Taftafa, B., Alsharif, M., Mhannayeh, A., Chinnappan, R., Alzhrani, A., Kazmi, S., Mir, M. S., Alsaud, A. W., et al. (2024) · Bioengineering · doi:10.3390/bioengineering11040346 · Cited by 15 · see citing works
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 15 · see citing works
Self-citationHuang, T. H., Huang, W. T., & Bian, Q. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114222 · Cited by 14 · see citing works
Bioengineering Liver Organoids for Diseases Modelling and Transplantation
Li, J., Chu, J., Lui, V. C. H., Chen, S., Chen, Y., & Tam, P. K. H. (2022) · Bioengineering · doi:10.3390/bioengineering9120796 · Cited by 14 · see citing works
Accelerated production of human epithelial organoids in a miniaturized spinning bioreactor
Ye, S., Marsee, A., van Tienderen, G. S., Rezaeimoghaddam, M., Sheikh, H., Samsom, R., de Koning, E. J. P., Fuchs, S. A., Verstegen, M. M. A., van der Laan, L. J. W., et al. (2024) · Cell Reports Methods · doi:10.1016/j.crmeth.2024.100903 · Cited by 15 · see citing works
Self-citationXie, Y., Tang, C., Huang, Z., Zhou, S., Yang, Y., Yin, Z., Heng, B. C., Chen, W., Chen, X., & Shen, W. (2021) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2021.0066 · Cited by 13 · see citing works
Cholangiocyte organoids to study drug-induced injury
Wang, Z., Xing, C., van der Laan, L. J. W., Verstegen, M. M. A., Spee, B., & Masereeuw, R. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03692-6 · Cited by 13 · see citing works
Self-citationRegenerative medicine for the hepatobiliary system: A review
Huang, Y. G., Miyamoto, D., Hidaka, M., Adachi, T., Gu, W., & Eguchi, S. (2020) · Journal of Hepato-Biliary-Pancreatic Sciences · doi:10.1002/jhbp.882 · Cited by 13 · see citing works
Microbiome-derived bile acids as endogenous regenerative mediators in liver repair
Pandey, S. N., Goyal, K., Rana, M., Menon, S. V., Ray, S., Ali, H., Kumbhar, P., Disouza, J., Singh, S. K., Gupta, G., et al. (2025) · Regenerative Therapy · doi:10.1016/j.reth.2025.08.011 · Cited by 12 · see citing works
Toward Transplantation of Liver Organoids: From Biology and Ethics to Cost-effective Therapy
ten Dam, M. J. M., Frederix, G., ten Ham, R. M. T., van der Laan, L. J. W., & Schneeberger, K. (2023) · Transplantation · doi:10.1097/tp.0000000000004520 · Cited by 12 · see citing works
Self-citationTong, Y., Ueyama-Toba, Y., Yokota, J., Matsui, H., Kanai, M., & Mizuguchi, H. (2024) · Scientific Reports · doi:10.1038/s41598-024-61544-y · Cited by 12 · see citing works
Exploring tumor organoids for cancer treatment
Jin, H., Yang, Q., Yang, J., Wang, F., Feng, J., Lei, L., & Dai, M. (2024) · APL Materials · doi:10.1063/5.0216185 · Cited by 11 · see citing works
Ueyama-Toba, Y., Tong, Y., Yokota, J., Murai, K., Hikita, H., Eguchi, H., Takehara, T., & Mizuguchi, H. (2024) · iScience · doi:10.1016/j.isci.2024.110778 · Cited by 11 · see citing works
Krüger, M., Samsom, R., Oosterhoff, L. A., van Wolferen, M. E., Kooistra, H. S., Geijsen, N., Penning, L. C., Kock, L. M., Sainz‐Arnal, P., Baptista, P. M., et al. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17510 · Cited by 11 · see citing works
Self-citationNovel approaches to liver disease diagnosis and modeling
de Oliveira, A. G., & Fiorotto, R. (2020) · Translational Gastroenterology and Hepatology · doi:10.21037/tgh-20-109 · Cited by 10 · see citing works
Chemically Defined Organoid Culture System for Cholangiocyte Differentiation
Wang, Z., Ye, S., van der Laan, L. J. W., Schneeberger, K., Masereeuw, R., & Spee, B. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202401511 · Cited by 10 · see citing works
Self-citationTomofuji, K., Kondo, J., Onuma, K., Coppo, R., Horie, H., Oyama, K., Miyoshi, E., Fukumitsu, K., Ishii, T., Hatano, E., et al. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000134 · Cited by 9 · see citing works
Organoids in Dynamic Culture: Microfluidics and 3D Printing Technologies
Su, X., Wang, M., Yuan, R., Guo, L., Han, Y., Huang, C., Li, A., Kaplan, D. L., & Wang, X. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.4c02245 · Cited by 9 · see citing works
Zhang, S., Liu, L., Li, X., Zhou, T., Shi, Q., Li, D., & Ju, X. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-04101-8 · Cited by 8 · see citing works
Characterization of human nasal organoids from chronic rhinosinusitis patients
Ramezanpour, M., Bolt, H., Hon, K., Shaghayegh, G., Rastin, H., Fenix, K. A., Psaltis, A. J., Wormald, P., & Vreugde, S. (2022) · Biology Open · doi:10.1242/bio.059267 · Cited by 8 · see citing works
Better In Vitro Tools for Exploring Chlamydia trachomatis Pathogenesis
Filardo, S., Pietro, M. D., & Sessa, R. (2022) · Life · doi:10.3390/life12071065 · Cited by 7 · see citing works
Nah, H., Michell, A. R., Rogy, K. M., Lally, O. J., & Khetani, S. R. (2025) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2025.115737 · Cited by 10 · see citing works
Organoids as platforms for infectious disease research
Liu, K., Zhao, Y., Joloya, E. M., Artegiani, B., Bartfeld, S., Choi, Y. K., Han, Y., Hendriks, D. F. G., Hoogduijn, M. J., Hudson, J. E., et al. (2026) · Nature Reviews Bioengineering · doi:10.1038/s44222-026-00445-3 · Cited by 7 · see citing works
Chi, K. Y., & Kim, J. (2022) · Organoid · doi:10.51335/organoid.2022.2.e6 · Cited by 6 · see citing works
The native liver as inspiration to create superior in vitro hepatic models
Carpentier, N., Urbani, L., Dubruel, P., & Vlierberghe, S. V. (2023) · Biomaterials Science · doi:10.1039/d2bm01646j · 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
“This study aims to address these gaps by conducting a comprehensive temporal proteomic analysis of iHLOs at four critical stages of development: Days 7, 15, 30, and 45.”
Toolbox for creating three-dimensional liver models
Panchuk, I., & Smirnikhina, S. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150375 · Cited by 5 · see citing works
Li, K., Ren, K., Du, S., Gao, X., & Yu, J. (2024) · Technology in Cancer Research & Treatment · doi:10.1177/15330338241285097 · Cited by 5 · see citing works
- Authors
- Schneeberger, K., Sánchez‐Romero, N., Ye, S., van Steenbeek, F. G., Oosterhoff, L. A., Pla Palacin, I., Chen, C., van Wolferen, M. E., van Tienderen, G., Lieshout, R., Colemonts‐Vroninks, H., Schene, I., Hoekstra, R., Verstegen, M. M. A., van der Laan, L. J. W., Penning, L. C., Fuchs, S. A., Clevers, H., De Kock, J., Baptista, P. M., & Spee, B.
- Affiliations
- Utrecht University (NL)
- Instituto de Investigación Sanitaria Aragón (ES)
- Department of Clinical Sciences of Companion Animals,Faculty of Veterinary Medicine,Utrecht University,Utrecht,the Netherlands
- Instituto de Investigación Sanitaria Aragón (IIS Aragón),Zaragoza,Spain
- Royal Netherlands Academy of Arts and Sciences (NL)
- Erasmus MC (NL)
- Vrije Universiteit Brussel (BE)
- University Medical Center Utrecht (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Department of Surgery,Erasmus MC‐University Medical Center,Rotterdam,the Netherlands
- Department of In Vitro Toxicology and Dermato‐cosmetology,Faculty of Medicine and Pharmacy,Vrije Universiteit Brussel,Brussels,Belgium
- Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo (ES)
- Corresponding author
- Schneeberger, Kerstin
- ORCID
- Venue
- Hepatology
- Published
- 2020-04-08
- Volume
- 72
- Issue
- 1
- Pages
- 257-270
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC7496924
- OpenAlex
- W2988904063
- Cited by
- 141
- References
- 33
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 27 · 2023: 21 · 2022: 28 · 2021: 27 · 2020: 10
- FWCI
- 10.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, cc-by-nc-nd)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- e-Archivo (Carlos III University of Madrid) (submittedVersion, cc-by-nc-nd)
- Zaguan (University of Zaragoza Repository) (submittedVersion, cc-by-nc-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- European Commission (HORIZON2020, 874586)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.Veni.198.021, 15498, 116004121)
- China Scholarship Council (CSC201306310019, CSC201808310180)
- Stichting voor de Technische Wetenschappen (15498)
- Instituto de Salud Carlos III (PI15/00563, PI18/00529)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- human liver organoids, spinner flask culture, organoid expansion, hepatocyte differentiation, cytochrome P450 activity, liver regeneration, liver transplantation, tissue engineering
- MeSH terms
- Cell Differentiation, Cells, Cultured, Humans, Liver Regeneration, Organoids, Stem Cells, Liver Transplantation, Cell Culture Techniques, Hepatocytes, Tissue Engineering, Receptors, G-Protein-Coupled, Cell Proliferation
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