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Cell diversity and network dynamics in photosensitive human brain organoids
Open accessAbstract
In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.
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“Although such regional diversity is appealing, it also leads to a relatively variable outcome and the differentiation of some cells into non-ectodermal cell types28,29.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
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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 [28]
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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 [107]
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 [28]
In the citing paper
“One important issue is that organoids derived from the same cell line under the same conditions can often produce tissues with different regional identities and spatial and cellular heterogeneity28,29.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“A recent paper used droplet-based single-cell mRNA sequencing to analyse gene expression in 80,000 cells from 31 brain organoids after 3 and 6 months in vitro28. Using principal component analysis, 10 distinct populations of cells (clusters) were identified in 6-month old organoids.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“As one might expect, 6-month-old organoids presented a greater diversity of cell types than 3-month-old organoids, as well as enrichment of genes associated with neuronal and glial maturation.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“Recently, it was demonstrated that photosensitive cells in retinal-like regions of brain organoids can respond to light28.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“Also, the authors observed that some cell types were only produced by a subset of organoids and that organoids grown in the same bioreactor tended to be similar in terms of their ability to make cells of each cluster, suggesting that batch effects and local microenvironments are important in patterning and possibly that organoids secrete signalling factors that influence sister organoids.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“In addition to these findings, electrophysiological studies have demonstrated functional synapses in several brain organoid models25,28, and electron microscopy has confirmed the presence of structurally defined synaptic junctions28.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“Several reports suggest that long-term organoid culture can improve the correlation between the molecular signatures of organoid and endogenous cells28,52.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“For example, a large number of cells were assigned to a mesodermal lineage, emphasizing the variability inherent in the protocol.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [28]
In the citing paper
“These initial reports identified striking parallels among organoid development, human primary tissue and in vivo organogenesis”
From The organoid cell atlas (2021) · cites this paper as [10]
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Citations
Cites
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Cerebral organoids model human brain development and microcephaly
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“Cluster c9 (17,103 cells) contained progenitors of neuroepithelial origin, including cells with an oligodendrocyte-precursor-like identity 20,26 .”
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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
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Lancaster, M. A., & Knoblich, J. A. (2014) · Nature Protocols · doi:10.1038/nprot.2014.158 · Cited by 1,823
Cited by
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Reactive 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
Is it time to start transitioning from 2D to 3D cell culture?
Jensen, C., & Teng, Y. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00033 · Cited by 1,640
Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity
Welch, J. D., Kozareva, V., Ferreira, A., Vanderburg, C., Martin, C., & Macosko, E. Z. (2019) · Cell · doi:10.1016/j.cell.2019.05.006 · Cited by 1,193
Self-citationAn in vivo model of functional and vascularized human brain organoids
Mansour, A. A., Gonçalves, J. T., Bloyd, C. W., Li, H., Fernandes, S., Quang, D., Johnston, S., Parylak, S. L., Jin, X., & Gage, F. H. (2018) · Nature Biotechnology · doi:10.1038/nbt.4127 · Cited by 1,211
Progress and potential in organoid research
Rossi, G., Manfrin, A., & Lutolf, M. P. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0051-9 · Cited by 1,182
Metadata
- Authors
- 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., Boyden, E. S., Lichtman, J. W., Williams, Z. M., McCarroll, S. A., & Arlotta, P.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Leaflabs (United States) (US)
- McGovern Institute for Brain Research (US)
- Corresponding author
- Quadrato, Giorgia
- Arlotta, Paola
- ORCID
- Venue
- Nature
- Published
- 2017-04-26
- Volume
- 545
- Issue
- 7652
- Pages
- 48-53
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5659341
- OpenAlex
- W2609844460
- Cited by
- 1,321
- References
- 45
- Citations by year
- 2026: 118 · 2025: 131 · 2024: 167 · 2023: 131 · 2022: 162 · 2021: 168 · 2020: 178 · 2019: 137 · 2018: 91 · 2017: 35
- FWCI
- 51.12
- 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)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institute of Mental Health (P50MH094271)
- National Institute of Neurological Disorders and Stroke (DP1NS087724, R01NS073124)
- 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 › Single-cell and spatial transcriptomics
- Keywords
- human brain organoids, cellular diversity, neuronal network dynamics, spontaneous neuronal activity, photostimulation, dendritic spines, cortical development, retinal development, single-cell gene expression, pluripotent stem cell differentiation, interneuron migration, synaptogenesis
- MeSH terms
- Brain, Cell Line, Cell Separation, Cerebral Cortex, Dendrites, Humans, Light, Nerve Net, Neural Pathways, Organ Specificity, Organoids, Retina, Time Factors, Sequence Analysis, RNA, Photoreceptor Cells, Vertebrate, Gene Expression Profiling, Pluripotent Stem Cells, Neurogenesis, Single-Cell Analysis, Transcriptome, In Vitro Techniques
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