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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Human brain organoids can replicate the complex brain microenvironment better than 2D in vitro models.
“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]
The Introduction describes 3D organoids with interacting brain-region identities and organization resembling the developing human brain; the Results report complex, heterogeneous tissues. These passages support the claim that organoids reproduce aspects of brain structure, but they do not establish that organoids replicate the brain microenvironment better than 2D in vitro models. (LLM, conf=0.84)
Experimental — accuracy not yet measuredhiPSC-derived astrocytes can be generated with a fast protocol in 2D layers or integrated in 3D systems such as spheroids and organoids.
“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]
The Results section (‘Generation of cerebral organoids’; page unavailable) reports 3D cerebral organoids generated from human induced pluripotent stem cells. It does not report hiPSC-derived astrocytes being integrated into those organoids or into spheroids. The fast 2D protocol is attached to a different citation and is not assessed here. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHuman disease models for liver, pancreas, CNS, skin, lung, intestine, musculoskeletal system and heart exist, yet whether they equal or surpass animal models remains unproven.
“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]
3D organoids often have instructive morphogenetic cues resulting in self organization similarly found in vivo.
“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]
Human brain organoids are 3D cultures derived from human pluripotent stem cells and recapitulate native brain cellular components, cytoarchitecture, and exhibit neural activity.
“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]
Organoid development followed the expected temporal changes.
“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
Organoids are limited by phenotypic variability and low throughput.
“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]
Brain organoids recapitulate early brain development and generate diverse cell types found in vivo.
“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]
APOE3Ch organoids stained prominently with Reelin, a marker of more mature neurons.
“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
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 current protocols.
“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]
Scaffold support provided by the extracellular matrix is an important feature of current protocols.
“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]
These protocols generated organoids with a dorsalized neuroepithelium that reproduced certain structural and cell-behaviour aspects of cortical development.
“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]
Protocols using medium free of neural induction signalling molecules promote generation of diverse brain regions and cell populations.
“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]
Bioreactors designed to improve oxygen diffusion and nutrient distribution produce larger and more viable structures that can grow for longer periods.
“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]
Cerebral organoids grown from iPSCs of a microcephalic patient carrying a CDK5RAP2 mutation had fewer proliferating progenitor cells and showed premature neural differentiation compared with wild-type cells.
“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]
The developmental timing of cortical neurogenesis appears conserved in vitro and has been demonstrated with both suspension and adherent differentiation methods.
“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]
UBA1 is broadly expressed in the human body, and its loss-of-function mutations are associated with neurodegenerative diseases.
“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]
Cerebral or other unguided neural organoids develop from ES or iPS cells into a three-dimensional neuroepithelium that self-patterns, regionalizes and forms neurons of different brain regions.
“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]
Self-organizing neural organoids grown from pluripotent stem cells combined with single-cell genomic technologies provide opportunities to examine gene regulatory networks underlying human brain development.
“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]
Brain organoids have been used to successfully model microcephaly, periventricular heterotopia, autism and other neurodevelopmental disorders that may have differential effects on various human brain regions.
“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]
iPSC models of rare microcephaly syndromes show loss of neuronal progenitor cells and premature neural differentiation.
“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
Three-dimensional brain organoids derived from human pluripotent stem cells have shown significant advantages in modeling neurological disorders including autism, microcephaly and Parkinson's disease.
“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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“Organoid cultures are small functional tissue units comprised of several distinct cell types that can be maintained and used to recapitulate features of tissues rather than that of individual cell types in vitro (Lancaster et al., 2013; Sato et al., 2011; Sato et al., 2009) (reviewed in (Lancaster and Knoblich, 2014)…”
BackgroundHuman organoids in basic research and clinical applications
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- 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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