Brain organoids: advances, applications and challenges
Open accessAbstract
Brain organoids are self-assembled three-dimensional aggregates generated from pluripotent stem cells with cell types and cytoarchitectures that resemble the embryonic human brain. As such, they have emerged as novel model systems that can be used to investigate human brain development and disorders. Although brain organoids mimic many key features of early human brain development at molecular, cellular, structural and functional levels, some aspects of brain development, such as the formation of distinct cortical neuronal layers, gyrification, and the establishment of complex neuronal circuitry, are not fully recapitulated. Here, we summarize recent advances in the development of brain organoid methodologies and discuss their applications in disease modeling. In addition, we compare current organoid systems to the embryonic human brain, highlighting features that currently can and cannot be recapitulated, and discuss perspectives for advancing current brain organoid technologies to expand their applications.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The small size of current organoids remains a limiting factor that restricts their ability to fully recapitulate the late stages of human organ development.
“Nevertheless, the small size of current organoids remains a limiting factor that restricts their ability to fully recapitulate the late stages of human organ development [19].”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [19]
Human primary tissue organoids range in size from a few hundred micrometers to a few millimeters and do not grow beyond a few millimeters in culture.
“Human primary tissue organoids range in size from a few hundred micrometers to a few millimeters (mm) and do not grow beyond a few millimeters in culture.”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [19]
Stem cell models have faced inherent constraints in recapitulating in vivo cellular diversity and the organization of neuronal-glial interactions.
“Despite advances in modeling Ts21, murine systems have limited translational relevance to human-specific aspects of neurodevelopment and cortical circuitry (7), whereas stem cell models have faced inherent constraints in recapitulating in vivo cellular diversity and the organization of neuronal-glial interactions (8, 9).”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [9]
Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133 · see citing works
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · see citing works
Cerebral organoids model human brain development and microcephaly
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., & Knoblich, J. A. (2013) · Nature · doi:10.1038/nature12517 · Cited by 5,372 · see citing works
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G. J., van Es, J. H., van den Brink, S., van Houdt, W. J., Pronk, A., van Gorp, J., Siersema, P. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.050 · Cited by 3,753 · see citing works
Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure
Qian, X., Nguyen, H. N., Song, M. M., Hadiono, C., Ogden, S. C., Hammack, C., Yao, B., Hamersky, G. R., Jacob, F., Zhong, C., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.032 · Cited by 2,127 · see citing works
Self-citationFunctional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture
Paşca, A. M., Sloan, S. A., Clarke, L. E., Tian, Y., Makinson, C. D., Huber, N., Kim, C. H., Park, J.-Y., O'Rourke, N. A., Nguyen, K. D., et al. (2015) · Nature Methods · doi:10.1038/nmeth.3415 · Cited by 1,609 · see citing works
Eiraku, M., Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Matsumura, M., Wataya, T., Nishiyama, A., Muguruma, K., & Sasai, Y. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.09.002 · Cited by 1,522 · see citing works
Designer 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
Neurogenic radial glia in the outer subventricular zone of human neocortex
Hansen, D. V., Lui, J. H., Parker, P. R. L., & Kriegstein, A. R. (2010) · Nature · doi:10.1038/nature08845 · Cited by 1,388 · see citing works
Assembly of functionally integrated human forebrain spheroids
Birey, F., Andersen, J., Makinson, C. D., Islam, S., Wei, W., Huber, N., Fan, H. C., Metzler, K. R. C., Panagiotakos, G., Thom, N., et al. (2017) · Nature · doi:10.1038/nature22330 · Cited by 1,365 · see citing works
The Brazilian Zika virus strain causes birth defects in experimental models
Cugola, F. R., Fernandes, I. R., Russo, F. B., Freitas, B. C., Dias, J. L. M., Guimarães, K. P., Benazzato, C., Almeida, N., Pignatari, G. C., Romero, S., et al. (2016) · Nature · doi:10.1038/nature18296 · Cited by 1,326 · see citing works
Cell diversity and network dynamics in photosensitive human brain organoids
Quadrato, G., Nguyen, T., Macosko, E. Z., Sherwood, J. L., Min Yang, S., Berger, D. R., Maria, N., Scholvin, J., Goldman, M., Kinney, J. P., et al. (2017) · Nature · doi:10.1038/nature22047 · Cited by 1,321 · see citing works
A three-dimensional human neural cell culture model of Alzheimer’s disease
Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D’Avanzo, C., Chen, H., Hooli, B., Asselin, C., Muffat, J., et al. (2014) · Nature · doi:10.1038/nature13800 · Cited by 1,195 · see citing works
Kadoshima, T., Sakaguchi, H., Nakano, T., Soen, M., Ando, S., Eiraku, M., & Sasai, Y. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315710110 · Cited by 999 · see citing works
Development of the human cerebral cortex: Boulder Committee revisited
Bystron, I., Blakemore, C., & Rakic, P. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2252 · Cited by 977 · see citing works
Fused cerebral organoids model interactions between brain regions
Bagley, J. A., Reumann, D., Bian, S., Lévi-Strauss, J., & Knoblich, J. A. (2017) · Nature Methods · doi:10.1038/nmeth.4304 · Cited by 790 · see citing works
Human iPSC-based modeling of late-onset disease via progerin-induced aging
Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J.-W., Kriks, S., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.11.006 · Cited by 777 · see citing works
Nakagawa, M., Taniguchi, Y., Senda, S., Takizawa, N., Ichisaka, T., Asano, K., Morizane, A., Doi, D., Takahashi, J., Nishizawa, M., et al. (2014) · Scientific Reports · doi:10.1038/srep03594 · Cited by 673 · see citing works
Human-specific gene <i>ARHGAP11B</i> promotes basal progenitor amplification and neocortex expansion
Florio, M., Albert, M., Taverna, E., Namba, T., Brandl, H., Lewitus, E., Haffner, C., Sykes, A., Wong, F. K., Peters, J., et al. (2015) · Science · doi:10.1126/science.aaa1975 · Cited by 632 · see citing works
Sloan, S. A., Darmanis, S., Huber, N., Khan, T. A., Birey, F., Caneda, C., Reimer, R., Quake, S. R., Barres, B. A., & Paşca, S. P. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.035 · Cited by 593 · see citing works
Raja, W. K., Mungenast, A. E., Lin, Y.-T., Ko, T., Abdurrob, F., Seo, J., & Tsai, L.-H. (2016) · PLOS ONE · doi:10.1371/journal.pone.0161969 · Cited by 569 · see citing works
Bershteyn, M., Nowakowski, T. J., Pollen, A. A., Di Lullo, E., Nene, A., Wynshaw-Boris, A., & Kriegstein, A. R. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2016.12.007 · Cited by 566 · see citing works
Synthetic hydrogels for human intestinal organoid generation and colonic wound repair
Cruz-Acuña, R., Quirós, M., Farkas, A. E., Dedhia, P. H., Huang, S., Siuda, D., García-Hernández, V., Miller, A. J., Spence, J. R., Nusrat, A., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3632 · Cited by 558 · see citing works
Sakaguchi, H., Kadoshima, T., Soen, M., Narii, N., Ishida, Y., Ohgushi, M., Takahashi, J., Eiraku, M., & Sasai, Y. (2015) · Nature Communications · doi:10.1038/ncomms9896 · Cited by 542 · see citing works
Reliability of human cortical organoid generation
Yoon, S.-J., Elahi, L. S., Pașca, A. M., Marton, R. M., Gordon, A., Revah, O., Miura, Y., Walczak, E. M., Holdgate, G. M., Fan, H. C., et al. (2019) · Nature Methods · doi:10.1038/s41592-018-0255-0 · Cited by 507 · see citing works
Comprehensive cellular‐resolution atlas of the adult human brain
Ding, S., Royall, J. J., Sunkin, S. M., Ng, L., Facer, B. A. C., Lesnar, P., Guillozet‐Bongaarts, A., McMurray, B., Szafer, A., Dolbeare, T. A., et al. (2016) · Journal of Comparative Neurology · doi:10.1002/cne.24080 · Cited by 447 · see citing works
Derivation of Human Midbrain-Specific Organoids from Neuroepithelial Stem Cells
Monzel, A. S., Smits, L. M., Hemmer, K., Hachi, S., Moreno, E. L., van Wuellen, T., Jarazo, J., Walter, J., Brüggemann, I., Boussaad, I., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.03.010 · Cited by 435 · see citing works
Modeling amyloid beta and tau pathology in human cerebral organoids
Gonzalez, C., Armijo, E., Bravo-Alegria, J., Becerra-Calixto, A., Mays, C. E., & Soto, C. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0229-8 · Cited by 430 · see citing works
Zeng, H., Shen, E. H., Hohmann, J. G., Oh, S. W., Bernard, A., Royall, J. J., Glattfelder, K. J., Sunkin, S. M., Morris, J. A., Guillozet-Bongaarts, A. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.052 · Cited by 426 · see citing works
Watanabe, M., Buth, J. E., Vishlaghi, N., de la Torre-Ubieta, L., Taxidis, J., Khakh, B. S., Coppola, G., Pearson, C. A., Yamauchi, K., Gong, D., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.047 · Cited by 401 · see citing works
Subcortical origins of human and monkey neocortical interneurons
Ma, T., Wang, C., Wang, L., Zhou, X., Tian, M., Zhang, Q., Zhang, Y., Li, J., Liu, Z., Cai, Y., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3536 · Cited by 322 · see citing works
Self-citationZhou, T., Tan, L., Cederquist, G. Y., Fan, Y., Hartley, B. J., Mukherjee, S., Tomishima, M., Brennand, K. J., Zhang, Q., Schwartz, R. E., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.06.017 · Cited by 263 · see citing works
Bae, B.-I., Tietjen, I., Atabay, K. D., Evrony, G. D., Johnson, M. B., Asare, E., Wang, P. P., Murayama, A. Y., Im, K., Lisgo, S. N., et al. (2014) · Science · doi:10.1126/science.1244392 · Cited by 229 · cited 2× · see citing works
“…ventral forebrain Guided Stationary floating culture Birey et al., 2017 Fused cerebral organoids Dorsal and ventral forebrain Guided Orbital shaker Bagley et al., 2017 Medial ganglionic eminence organoid Medial ganglionic eminence Guided Orbital shaker Xiang et al., 2017 Organoid grafts in mouse…”
BackgroundStem cell models of Alzheimer’s disease: progress and challenges
Arber, C., Lovejoy, C., & Wray, S. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0268-4 · Cited by 143 · see citing works
Saito, T., Hanai, S., Takashima, S., Nakagawa, E., Okazaki, S., Inoue, T., Miyata, R., Hoshino, K., Akashi, T., Sasaki, M., et al. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhq125 · Cited by 76 · see citing works
Diversity of Cortical Interneurons in Primates: The Role of the Dorsal Proliferative Niche
Radonjić, N. V., Ayoub, A. E., Memi, F., Yu, X., Maroof, A., Jakovcevski, I., Anderson, S. A., Rakic, P., & Zecevic, N. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.11.026 · Cited by 74 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184 · see citing works
Towards organoid culture without Matrigel
Kozlowski, M. T., Crook, C. J., & Ku, H. T. (2021) · Communications Biology · doi:10.1038/s42003-021-02910-8 · Cited by 409 · see citing works
Bioengineering Approaches for the Advanced Organoid Research
Yi, S. A., Zhang, Y., Rathnam, C., Pongkulapa, T., & Lee, K. (2021) · Advanced Materials · doi:10.1002/adma.202007949 · Cited by 218 · see citing works
Papamichail, L., Koch, L. S., Veerman, D., Broersen, K., & van der Meer, A. D. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2025.1515340 · Cited by 120 · see citing works
Advanced human developmental toxicity and teratogenicity assessment using human organoid models
Li, M., Gong, J., Gao, L., Zou, T., Kang, J., & Xu, H. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.113429 · Cited by 84 · see citing works
Human iPSC-derived glia models for the study of neuroinflammation
Stöberl, N., Maguire, E., Salis, E., Shaw, B., & Hall-Roberts, H. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02919-2 · Cited by 71 · see citing works
Bartalska, K., Hübschmann, V., Korkut-Demirbaş, M., Cubero, R. J. A., Venturino, A., Rössler, K., Czech, T., & Siegert, S. (2022) · iScience · doi:10.1016/j.isci.2022.104580 · Cited by 22 · see citing works
The empowering influence of air-liquid interface culture on skin organoid hair follicle development
Sun, J., Ahmed, I., Brown, J., Khosrotehrani, K., & Shafiee, A. (2025) · Burns & Trauma · doi:10.1093/burnst/tkae070 · Cited by 19 · see citing works
Brain organoid methodologies to explore mechanisms of disease in progressive multiple sclerosis
Simões-Abade, M. B. C., Patterer, M., Nicaise, A. M., & Pluchino, S. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1488691 · Cited by 14 · see citing works
Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex
Risgaard, R. D., Hanthanan Arachchilage, K., Knaack, S. A., Hosseini, M., Chen, R. J., Kumarage, P., Schmidt, D. K., Huang, X., Sheng, J., Wang, C. J., et al. (2026) · Science · doi:10.1126/science.aea1549 · Cited by 12 · see citing works
Chimeric brain models to study human glial-neuronal and macroglial-microglial interactions
Jin, M., Ma, Z., Zhang, H., Dang, R., Papetti, A. V., Stillitano, A. C., Zou, L., Goldman, S. A., & Jiang, P. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116794 · Cited by 6 · see citing works
- Authors
- Qian, X., Song, H., & Ming, G.-L.
- Affiliations
- Johns Hopkins University (US)
- University of Pennsylvania (US)
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2019-04-15
- Volume
- 146
- Issue
- 8
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC6503989
- OpenAlex
- W2938519320
- Cited by
- 724
- References
- 37
- Citations by year
- 2026: 83 · 2025: 142 · 2024: 122 · 2023: 91 · 2022: 102 · 2021: 105 · 2020: 61 · 2019: 18
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (R37NS047344, P01NS097206, U19MH106434, R01MH105128, R35NS097370, U19AI131130)
- Simons Foundation (575050)
- Dr Miriam and Sheldon G. Adelson Medical Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- brain organoids, pluripotent stem cells, human brain development, disease modeling, cortical folding, neural circuits, 3D cell aggregates
- MeSH terms
- Animals, Brain, Humans, Models, Biological, Organoids
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
