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Cerebral organoids model human brain development and microcephaly
Open accessAbstract
The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.
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“With their 3D structures and cell components resembling the human brain, these organoids can replicate the complex brain microenvironment better than 2D in vitro models (15–17, 19)”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“hiPSC-derived astrocytes, which can be generated with a fast protocol in 2D layers104 or integrated in 3D systems such as spheroids and organoids105–108”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [106]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The differentiation protocol was further optimized by integrating established principles of neuronal development to ensure reproducibility and high neuronal purity (Lancaster et al. 2013;Lancaster and Knoblich 2014a;Lancaster and Knoblich 2014b).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Lancaster et al. 2013
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Promising disease models of the liver65,66, pancreas67,68, central nervous system35,69,70, skin71, lung72,73, intestine72–76, musculoskeletal system77 and heart78–81 have been developed, but their equivalence or superiority over their animal models needs to be demonstrated.”
From Human disease models in drug development (2023) · cites this paper as [35]
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In the citing paper
“Apart from growth factor cues, other modulators — such as scaffold support provided by the extracellular matrix — are important features of current protocols2,5,28.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [2]
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“These 3D “organoids” are often found to have instructive morphogenetic cues resulting in self organization similarly found in vivo [53,54].”
From Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy (2022) · cites this paper as [53]
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In the citing paper
“Human brain organoids are 3D cultures derived from human pluripotent stem cells and recapitulate native brain cellular components, cytoarchitecture, and exhibit neural activity.22–24”
From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [22]
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In the citing paper
“Organoid development followed the expected temporal changes (Lancaster et al., 2013; Velasco et al., 2019; Watanabe et al., 2017; Yoon et al., 2019; Figures 1B–1D; Figure S1A).”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Lancaster et al., 2013
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“Although organoids have been used to investigate disease-associated genes9–11, they are limited by phenotypic variability and low throughput.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [9]
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In the citing paper
“Brain organoids recapitulate early brain development and generate diverse cell types found in vivo9.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [9]
In the citing paper
“Consistent with a more mature phenotype, APOE3Ch organoids stained prominently with Reelin, a marker of more mature neurons (Figures 4A–D; Lancaster et al., 2013; Di Lullo and Kriegstein, 2017).”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Lancaster et al., 2013
In the citing paper
“The production of radial glial cells, intermediate progenitors, and deep- and superficial-layer neurons in an ordered temporal fashion has been reported by studies using all of the protocols currently in use2,3,5,25.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [2]
In the citing paper
“Both of these protocols generated organoids containing a dorsalized neuroepithelium that reproduced certain aspects of cortical development, both structurally and in terms of cell behaviour.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [2]
In the citing paper
“Some protocols build on the principles of spontaneous neural induction by using medium that is free of neural induction signalling molecules2,27. This promotes the generation of diverse brain regions and cell populations2,28,29.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [2]
In the citing paper
“Bioreactors designed to improve oxygen diffusion and nutrient distribution have been used to produce larger and more viable structures that can grow for longer periods2,5 (BOX 1).”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [2]
In the citing paper
“Cerebral organoids grown from these cells contained fewer proliferating progenitor cells and showed premature neural differentiation compared to wild-type counterparts.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [2]
In the citing paper
“Interestingly, the developmental timing of cortical neurogenesis appears to be conserved in vitro and has been demonstrated with both suspension and adherent differentiation methods2,3,5,39.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [2]
In the citing paper
“Intriguingly, UBA1 is widely expressed in the human body, but loss-of-function mutations are linked to neurodegenerative diseases110.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [110]
In the citing paper
“Cerebral or other unguided neural organoids develop from embryonic stem (ES) cells or induced pluripotent stem (iPS) cells into a three-dimensional neuroepithelium that self-patterns, regionalizes and, ultimately, forms neurons of the different brain regions1–3.”
From Inferring and perturbing cell fate regulomes in human brain organoids (2023) · cites this paper as [2]
In the citing paper
“Self-organizing neural organoids grown from pluripotent stem cells1–3 combined with single-cell genomic technologies provide opportunities to examine gene regulatory networks underlying human brain development.”
From Inferring and perturbing cell fate regulomes in human brain organoids (2023) · cites this paper as [2]
In the citing paper
“Brain organoids have been used to successfully model microcephaly2, periventricular heterotopia10, autism11 and other neurodevelopmental disorders12,13 that may have differential effects on the various human brain regions.”
From Inferring and perturbing cell fate regulomes in human brain organoids (2023) · cites this paper as [2]
In the citing paper
“IPSC models of rare microcephaly syndromes have been shown to undergo loss of neuronal progenitor cells and premature neural differentiation (Lancaster et al., 2013).”
From Getting to the cores of autism (2019) · cites this paper as Lancaster et al., 2013
In the citing paper
“Three-dimensional brain organoids derived from human pluripotent stem cells (hPSCs) have shown significant advantages in modeling neurological disorders including autism, microcephaly and Parkinson’s disease.528–530”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [528]
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Citations
Cites
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Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
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Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,519
The cell biology of neurogenesis
Götz, M., & Huttner, W. B. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1739 · Cited by 2,130
A ROCK inhibitor permits survival of dissociated human embryonic stem cells
Watanabe, K., Ueno, M., Kamiya, D., Nishiyama, A., Matsumura, M., Wataya, T., Takahashi, J. B., Nishikawa, S., Nishikawa, S.-I., Muguruma, K., et al. (2007) · Nature Biotechnology · doi:10.1038/nbt1310 · Cited by 2,055
Self-organizing optic-cup morphogenesis in three-dimensional culture
Eiraku, M., Takata, N., Ishibashi, H., Kawada, M., Sakakura, E., Okuda, S., Sekiguchi, K., Adachi, T., & Sasai, Y. (2011) · Nature · doi:10.1038/nature09941 · Cited by 2,001
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
Self-formation of optic cups and storable stratified neural retina from human ESCs
Nakano, T., Ando, S., Takata, N., Kawada, M., Muguruma, K., Sekiguchi, K., Saito, K., Yonemura, S., Eiraku, M., & Sasai, Y. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.05.009 · Cited by 1,447
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
Cited by
Sorted by citations
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,519
Bhatia, S. N., & Ingber, D. E. (2014) · Nature Biotechnology · doi:10.1038/nbt.2989 · Cited by 3,305
Modeling Development and Disease with Organoids
Clevers, H. (2016) · Cell · doi:10.1016/j.cell.2016.05.082 · Cited by 3,196
Organogenesis in a dish: Modeling development and disease using organoid technologies
Lancaster, M. A., & Knoblich, J. A. (2014) · Science · doi:10.1126/science.1247125 · Cited by 2,931
Self-citationReactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,513
Metadata
- Authors
- 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.
- Affiliations
- Institute of Molecular Biotechnology (AT)
- Institute of Genetics and Cancer (GB)
- Wellcome Sanger Institute (GB)
- St George's, University of London (GB)
- Corresponding author
- Knoblich, Juergen A.
- ORCID
- Venue
- Nature
- Published
- 2013-08-28
- Volume
- 501
- Issue
- 7467
- Pages
- 373-379
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3817409
- OpenAlex
- W2018286352
- Cited by
- 5,372
- References
- 57
- Citations by year
- 2026: 446 · 2025: 575 · 2024: 543 · 2023: 560 · 2022: 544 · 2021: 572 · 2020: 512 · 2019: 383 · 2018: 346 · 2017: 302 · 2016: 239 · 2015: 175 · 2014: 138 · 2013: 31
- FWCI
- 72.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (WT 098051)
- Lister Institute of Preventive Medicine
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- brain organoids, human brain development, microcephaly, pluripotent stem cells, induced pluripotent stem cells, three-dimensional organoid culture, cortical development, neuronal differentiation, patient-derived disease model
- MeSH terms
- Animals, Brain, Cerebral Cortex, Humans, Microcephaly, Models, Biological, Neurons, Organoids, Tissue Culture Techniques, Mice, Neurogenesis, Induced Pluripotent Stem Cells, Neural Stem Cells
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