Lancaster, M. A. Unraveling mechanisms of human brain evolution. Cell 187, 5838–5857 (2024).
Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).
Eiraku, M. et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3, 519–532 (2008).
Antón-Bolaños, N. et al. Brain chimeroids reveal individual susceptibility to neurotoxic triggers. Nature 631, 142–149 (2024).
Kanton, S. et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature 574, 418–422 (2019).
Otani, T., Marchetto, M. C., Gage, F. H., Simons, B. D. & Livesey, F. J. 2D and 3D stem cell models of primate cortical development identify species-specific differences in progenitor behavior contributing to brain size. Cell Stem Cell 18, 467–480 (2016).
Mora-Bermúdez, F. et al. Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development. eLife 5, e18683 (2016).
Pollen, A. A. et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell 176, 743–756.e17 (2019).
de Sousa, A. A. et al. Comparative cytoarchitectural analyses of striate and extrastriate areas in hominoids. Cereb. Cortex 20, 966–981 (2010).
Dicke, U. & Roth, G. Neuronal factors determining high intelligence. Phil. Trans. R. Soc. B 371, 20150180 (2016).
Benito-Kwiecinski, S. et al. An early cell shape transition drives evolutionary expansion of the human forebrain. Cell 184, 2084–2102.e19 (2021).
She, R. et al. Comparative landscape of genetic dependencies in human and chimpanzee stem cells. Cell 186, 2977–2994.e23 (2023).
Pollard, K. S. et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443, 167–172 (2006).
Dennis, M. Y. et al. Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell 149, 912–922 (2012).
Suzuki, I. K. et al. Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation. Cell 173, 1370–1384.e16 (2018).
Fiddes, I. T. et al. Human-specific NOTCH2NL genes affect Notch signaling and cortical neurogenesis. Cell 173, 1356–1369.e22 (2018).
Florio, M. et al. Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. Science 347, 1465–1470 (2015).
Boyd, J. L. et al. Human–chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex. Curr. Biol. 25, 772–779 (2015).
Fischer, J. et al. Human-specific ARHGAP11B ensures human-like basal progenitor levels in hominid cerebral organoids. EMBO Rep. 23, e54728 (2022).
Haygood, R., Babbitt, C. C., Fedrigo, O. & Wray, G. A. Contrasts between adaptive coding and noncoding changes during human evolution. Proc. Natl Acad. Sci. USA 107, 7853–7857 (2010).
Parenti, I., Rabaneda, L. G., Schoen, H. & Novarino, G. Neurodevelopmental disorders: from genetics to functional pathways. Trends Neurosci. 43, 608–621 (2020).
Dang, L. T. et al. STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation. Dev. Neurobiol. 81, 696–709 (2021).
Zhang, W. et al. Cerebral organoid and mouse models reveal a RAB39b–PI3K–mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes. Genes Dev. 34, 580–597 (2020).
Dhaliwal, N., Choi, W. W. Y., Muffat, J. & Li, Y. Modeling PTEN overexpression-induced microcephaly in human brain organoids. Mol. Brain 14, 131 (2021).
Omer Javed, A. et al. Microcephaly modeling of kinetochore mutation reveals a brain-specific phenotype. Cell Rep. 25, 368–382.e5 (2018).
Fair, S. R. et al. Cerebral organoids containing an AUTS2 missense variant model microcephaly. Brain 146, 387–404 (2023).
Wang, L. et al. Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly. Nat. Commun. 11, 4038 (2020).
Esk, C. et al. A human tissue screen identifies a regulator of ER secretion as a brain-size determinant. Science 370, 935–941 (2020).
Bershteyn, M. et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell 20, 435–449.e4 (2017).
Iefremova, V. et al. An organoid-based model of cortical development identifies non-cell-autonomous defects in Wnt signaling contributing to Miller–Dieker syndrome. Cell Rep. 19, 50–59 (2017).
Karzbrun, E., Kshirsagar, A., Cohen, S. R., Hanna, J. H. & Reiner, O. Human brain organoids on a chip reveal the physics of folding. Nat. Phys. 14, 515–522 (2018).
O’Neill, A. C. et al. Mob2 insufficiency disrupts neuronal migration in the developing cortex. Front. Cell Neurosci. 12, 57 (2018).
Buchsbaum, I. Y. et al. ECE2 regulates neurogenesis and neuronal migration during human cortical development. EMBO Rep. 21, e48204 (2020).
Klaus, J. et al. Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. Nat. Med. 25, 561–568 (2019).
Ayo-Martin, A. C., Kyrousi, C., Di Giaimo, R. & Cappello, S. GNG5 controls the number of apical and basal progenitors and alters neuronal migration during cortical development. Front. Mol. Biosci. 7, 578137 (2020).
Blair, J. D., Hockemeyer, D. & Bateup, H. S. Genetically engineered human cortical spheroid models of tuberous sclerosis. Nat. Med. 24, 1568–1578 (2018).
Eichmüller, O. L. et al. Amplification of human interneuron progenitors promotes brain tumors and neurological defects. Science 375, eabf5546 (2022).
Marchetto, M. C. N. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Mellios, N. et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol. Psychiatry 23, 1051–1065 (2018).
Trujillo, C. A. et al. Pharmacological reversal of synaptic and network pathology in human MECP2‐KO neurons and cortical organoids. EMBO Mol. Med. 13, e12523 (2021).
Gomes, A. R. et al. Modeling Rett syndrome with human patient-specific forebrain organoids. Front. Cell Dev. Biol. 8, 610427 (2020).
Xiang, Y. et al. Dysregulation of BRD4 function underlies the functional abnormalities of MeCP2 mutant neurons. Mol. Cell 79, 84–98.e9 (2020).
Samarasinghe, R. A. et al. Identification of neural oscillations and epileptiform changes in human brain organoids. Nat. Neurosci. 24, 1488–1500 (2021).
Yildirim, M. et al. Label-free three-photon imaging of intact human cerebral organoids for tracking early events in brain development and deficits in Rett syndrome. eLife 11, e78079 (2022).
Birey, F. et al. Assembly of functionally integrated human forebrain spheroids. Nature 545, 54–59 (2017).
Birey, F. et al. Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome. Cell Stem Cell 29, 248–264.e7 (2022).
Miura, Y. et al. Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells. Nat. Biotechnol. 38, 1421–1430 (2020).
Kang, Y. et al. A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies. Nat. Neurosci. 24, 1377–1391 (2021).
Sun, A. X. et al. Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science 366, 1486–1492 (2019).
Khan, T. A. et al. Neuronal defects in a human cellular model of 22q11.2 deletion syndrome. Nat. Med. 26, 1888–1898 (2020).
Shin, D. et al. Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders. Cell Stem Cell 31, 421–432.e8 (2024).
Mariani, J. et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375–390 (2015).
Jourdon, A. et al. Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis. Nat. Neurosci. 26, 1505–1515 (2023).
Paulsen, B. et al. Autism genes converge on asynchronous development of shared neuron classes. Nature 602, 268–273 (2022).
Pigoni, M. et al. Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity. Hum. Mol. Genet. 32, 2773–2786 (2023).
Villa, C. E. et al. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Rep. 39, 110615 (2022).
Birtele, M. et al. Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis. Nat. Neurosci. 26, 2090–2103 (2023).
Li, C. et al. Single-cell brain organoid screening identifies developmental defects in autism. Nature 621, 373–380 (2023).
Meng, X. et al. Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment. Nature 622, 359–366 (2023).
Notaras, M. et al. Schizophrenia is defined by cell-specific neuropathology and multiple neurodevelopmental mechanisms in patient-derived cerebral organoids. Mol. Psychiatry 27, 1416–1434 (2022).
Qian, X. et al. Sliced human cortical organoids for modeling distinct cortical layer formation. Cell Stem Cell 26, 766–781.e9 (2020).
Ye, F. et al. DISC1 regulates neurogenesis via modulating kinetochore attachment of Ndel1/Nde1 during mitosis. Neuron 96, 1041–1054.e5 (2017).
Stachowiak, E. K. et al. Cerebral organoids reveal early cortical maldevelopment in schizophrenia—computational anatomy and genomics, role of FGFR1. Transl. Psychiatry 7, 6 (2017).
Srikanth, P. et al. Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids. Transl. Psychiatry 8, 77 (2018).
Kathuria, A. et al. Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder. Genome Med. 12, 34 (2020).
Yang, G. et al. Neurite outgrowth deficits caused by rare PLXNB1 mutation in pediatric bipolar disorder. Mol. Psychiatry 28, 2525–2539 (2023).
Osete, J. R. et al. Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids. Mol. Psychiatry 28, 3033–3043 (2023).
Hewitt, T. et al. Bipolar disorder iPSC-derived neural progenitor cells exhibit dysregulation of store-operated Ca2+ entry and accelerated differentiation. Mol. Psychiatry 28, 5327–5250 (2023).
Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).
Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).
Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016).
Dang, J. et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell 19, 258–265 (2016).
Xu, M. et al. Identification of small molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 22, 1101–1107 (2016).
Ramani, A. et al. SARS‐CoV‐2 targets neurons of 3D human brain organoids. EMBO J. 39, e106230 (2020).
Zhang, B.-Z. et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res. 30, 928–931 (2020).
Aschman, T., Mothes, R., Heppner, F. L. & Radbruch, H. What SARS-CoV-2 does to our brains. Immunity 55, 1159–1172 (2022).
Pellegrini, L. et al. SARS-CoV-2 infects the brain choroid plexus and disrupts the blood–CSF barrier in human brain organoids. Cell Stem Cell 27, 951–961.e5 (2020).
Jacob, F. et al. Human pluripotent stem cell-derived neural cells and brain organoids reveal SARS-CoV-2 neurotropism predominates in choroid plexus epithelium. Cell Stem Cell 27, 937–950.e9 (2020).
McMahon, C. L., Staples, H., Gazi, M., Carrion, R. & Hsieh, J. SARS-CoV-2 targets glial cells in human cortical organoids. Stem Cell Rep. 16, 1156–1164 (2021).
Wang, L. et al. A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology. Nat. Med. 27, 1600–1606 (2021).
Khan, M. et al. Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients. Neuron 110, 3919–3935.e6 (2022).
Fan, W., Christian, K. M., Song, H. & Ming, G. Applications of brain organoids for infectious diseases. J. Mol. Biol. 434, 167243 (2022).
Sun, G. et al. Modeling human cytomegalovirus-induced microcephaly in human ipsc-derived brain organoids. Cell Rep. Med. 1, 100002 (2020).
Krenn, V. et al. Organoid modeling of Zika and herpes simplex virus 1 infections reveals virus-specific responses leading to microcephaly. Cell Stem Cell 28, 1362 (2021).
Qiao, H. et al. Herpes simplex virus type 1 infection leads to neurodevelopmental disorder-associated neuropathological changes. PLoS Pathog. 16, e1008899 (2020).
dos Reis, R. S., Sant, S., Keeney, H., Wagner, M. C. E. & Ayyavoo, V. Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia. Sci. Rep. 10, 15209 (2020).
Robertson, K., Liner, J. & Meeker, R. B. Antiretroviral neurotoxicity. J. Neurovirol. 18, 388–399 (2012).
Etherton, M. R., Lyons, J. L. & Ard, K. L. HIV-associated neurocognitive disorders and antiretroviral therapy: current concepts and controversies. Curr. Infect. Dis. Rep. 17, 485 (2015).
Groveman, B. R. et al. Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt–Jakob disease. Sci. Rep. 11, 5165 (2021).
Velmeshev, D. et al. Single-cell analysis of prenatal and postnatal human cortical development. Science 382, eadf0834 (2023).
Madhavan, M. et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat. Methods 15, 700–706 (2018).
Marton, R. M. et al. Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat. Neurosci. 22, 484–491 (2019).
Chamling, X. et al. Single-cell transcriptomic reveals molecular diversity and developmental heterogeneity of human stem cell-derived oligodendrocyte lineage cells. Nat. Commun. 12, 652 (2021).
Shaker, M. R. et al. Rapid and efficient generation of myelinating human oligodendrocytes in organoids. Front. Cell Neurosci. 15, 631548 (2021).
Kim, H. et al. Pluripotent stem cell-derived cerebral organoids reveal human oligodendrogenesis with dorsal and ventral origins. Stem Cell Rep. 12, 890–905 (2019).
Kim, H. & Jiang, P. Generation of human pluripotent stem cell-derived fused organoids with oligodendroglia and myelin. Star. Protoc. 2, 100443 (2021).
Sloan, S. A. et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95, 779–790.e6 (2017).
Verkerke, M. et al. Transcriptomic and morphological maturation of human astrocytes in cerebral organoids. Glia 72, 362–374 (2024).
Bachiller, S. et al. Microglia in neurological diseases: a road map to brain-disease-dependent inflammatory response. Front. Cell Neurosci. 12, 488 (2018).
Ormel, P. R. et al. Microglia innately develop within cerebral organoids. Nat. Commun. 9, 4167 (2018).
Abud, E. M. et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293.e9 (2017).
Abreu, C. M. et al. Microglia increase inflammatory responses in iPSC-derived human brainspheres. Front. Microbiol. 9, 2766 (2018).
Muffat, J. et al. Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections. Proc. Natl Acad. Sci. USA 115, 7117–7122 (2018).
Song, L. et al. Functionalization of brain region-specific spheroids with isogenic microglia-like cells. Sci. Rep. 9, 11055 (2019).
Bejoy, J. et al. Genomics analysis of metabolic pathways of human stem cell-derived microglia-like cells and the integrated cortical spheroids. Stem Cell Int. 2019, 2382534 (2019).
Popova, G. et al. Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids. Cell Stem Cell 28, 2153–2166.e6 (2021).
Popova, G. et al. Rubella virus tropism and single-cell responses in human primary tissue and microglia-containing organoids. eLife 12, RP87696 (2023).
Schafer, S. T. et al. An in vivo neuroimmune organoid model to study human microglia phenotypes. Cell 186, 2111–2126.e20 (2023).
Sabate‐Soler, S. et al. Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality. Glia 70, 1267–1288 (2022).
Park, D. S. et al. iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer. Nature 623, 397–405 (2023).
Tata, M. & Ruhrberg, C. Cross-talk between blood vessels and neural progenitors in the developing brain. Neuronal Signal. 2, NS20170139 (2018).
Ham, O., Jin, Y. B., Kim, J. & Lee, M.-O. Blood vessel formation in cerebral organoids formed from human embryonic stem cells. Biochem. Biophys. Res. Commun. 521, 84–90 (2020).
Pham, M. T. et al. Generation of human vascularized brain organoids. Neuroreport 29, 588–593 (2018).
Shi, Y. et al. Vascularized human cortical organoids (vOrganoids) model cortical development in vivo. PLoS Biol. 18, e3000705 (2020).
Sun, X.-Y. et al. Generation of vascularized brain organoids to study neurovascular interactions. eLife 11, e76707 (2022).
Cakir, B. et al. Engineering of human brain organoids with a functional vascular-like system. Nat. Methods 16, 1169–1175 (2019).
Wimmer, R. A. et al. Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565, 505–510 (2019).
Grebenyuk, S. et al. Large-scale perfused tissues via synthetic 3D soft microfluidics. Nat. Commun. 14, 193 (2023).
Bagley, J. A., Reumann, D., Bian, S., Lévi-Strauss, J. & Knoblich, J. A. Fused dorsal–ventral cerebral organoids model complex interactions between diverse brain regions. Nat. Methods 14, 743–751 (2017).
Xiang, Y. et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 21, 383–398.e7 (2017).
Andersen, J. et al. Generation of functional human 3D cortico-motor assembloids. Cell 183, 1913–1929.e26 (2020).
Xiang, Y., Cakir, B. & Park, I.-H. Generation of regionally specified human brain organoids resembling thalamus development. Star. Protoc. 1, 100001 (2020).
Fligor, C. M. et al. Extension of retinofugal projections in an assembled model of human pluripotent stem cell-derived organoids. Stem Cell Rep. 16, 2228–2241 (2021).
Patton, M. H. et al. Synaptic plasticity in human thalamocortical assembloids. Cell Rep. 43, 114503 (2024).
Kim, J. et al. Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway. Neuron https://doi.org/10.1016/j.neuron.2024.09.020 (2024).
Reumann, D. et al. In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids. Nat. Methods 20, 2034 (2023).
Sood, D. et al. Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix. Sci. Rep. 9, 17874 (2019).
Fiorenzano, A. et al. Single-cell transcriptomics captures features of human midbrain development and dopamine neuron diversity in brain organoids. Nat. Commun. 12, 7302 (2021).
Sozzi, E. et al. Silk scaffolding drives self-assembly of functional and mature human brain organoids. Front. Cell Dev. Biol. 10, 1023279 (2022).
Kjar, A. et al. Biofunctionalized gelatin hydrogels support development and maturation of iPSC-derived cortical organoids. Cell Rep. 43, 114874 (2024).
Lancaster, M. A. et al. Guided self-organization and cortical plate formation in human brain organoids. Nat. Biotechnol. 35, 659–666 (2017).
Ritzau-Reid, K. I. et al. Microfibrous scaffolds guide stem cell lumenogenesis and brain organoid engineering. Adv. Mater. 35, 2300305 (2023).
Knight, G. T. et al. Engineering induction of singular neural rosette emergence within hPSC-derived tissues. eLife 7, e37549 (2018).
Karzbrun, E. et al. Human neural tube morphogenesis in vitro by geometric constraints. Nature 599, 268–272 (2021).
Wang, Y. et al. Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes. Nat. Commun. 13, 5688 (2022).
Tidball, A. M. et al. Deriving early single-rosette brain organoids from human pluripotent stem cells. Stem Cell Reports 18, 2498–2514 (2023).
Haremaki, T. et al. Self-organizing neuruloids model developmental aspects of Huntington’s disease in the ectodermal compartment. Nat. Biotechnol. 37, 1198–1208 (2019).
Fedorchak, N. J., Iyer, N. & Ashton, R. S. Bioengineering tissue morphogenesis and function in human neural organoids. Semin. Cell Dev. Biol. 111, 52–59 (2021).
Cho, A.-N. et al. Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids. Nat. Commun. 12, 4730 (2021).
Walsh, R. M. et al. Generation of human cerebral organoids with a structured outer subventricular zone. Cell Rep. 43, 114031 (2024).
Andrews, M. G. et al. LIF signaling regulates outer radial glial to interneuron fate during human cortical development. Cell Stem Cell 30, 1382–1391.e5 (2023).
Cederquist, G. Y. et al. Specification of positional identity in forebrain organoids. Nat. Biotechnol. 37, 436–444 (2019).
Uzel, S. G. M. et al. Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units. Sci. Adv. 2, e1501429 (2016).
Rifes, P. et al. Modeling neural tube development by differentiation of human embryonic stem cells in a microfluidic WNT gradient. Nat. Biotechnol. 38, 1265–1273 (2020).
Xue, X. et al. A patterned human neural tube model using microfluidic gradients. Nature 628, 391–399 (2024).
Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017).
Paşca, A. M. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671–678 (2015).
Giandomenico, S. L. et al. Cerebral organoids at the air–liquid interface generate diverse nerve tracts with functional output. Nat. Neurosci. 22, 669–679 (2019).
Osaki, T. et al. Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons. Nat. Commun. 15, 2945 (2024).
Kirihara, T. et al. A human induced pluripotent stem cell-derived tissue model of a cerebral tract connecting two cortical regions. iScience 14, 301–311 (2019).
Harris, J. M. et al. Long-range optogenetic control of axon guidance overcomes developmental boundaries and defects. Dev. Cell 53, 577–588.e7 (2020).
Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432–441 (2018).
Revah, O. et al. Maturation and circuit integration of transplanted human cortical organoids. Nature 610, 319–326 (2022).
Wilson, M. N. et al. Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex. Nat. Commun. 13, 7945 (2022).
Atamian, A., Cordón-Barris, L. & Quadrato, G. Taming human brain organoids one cell at a time. Semin. Cell Dev. Biol. 111, 23–31 (2021).
Velasco, S. et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature 570, 523–527 (2019).
Yoon, J. H., Minzenberg, M. J., Raouf, S., D’Esposito, M. & Carter, C. S. Impaired prefrontal-basal ganglia functional connectivity and substantia nigra hyperactivity in schizophrenia. Biol. Psychiatry 74, 122–129 (2013).
Bock, C. et al. The organoid cell atlas. Nat. Biotechnol. 39, 13–17 (2021).
Cheroni, C. et al. Benchmarking brain organoid recapitulation of fetal corticogenesis. Transl. Psychiatry 12, 520 (2022).
Tanaka, Y., Cakir, B., Xiang, Y., Sullivan, G. J. & Park, I.-H. Synthetic analyses of single-cell transcriptomes from multiple brain organoids and fetal brain. Cell Rep. 30, 1682–1689.e3 (2020).
Bhaduri, A. et al. Cell stress in cortical organoids impairs molecular subtype specification. Nature 578, 142–148 (2020).
Uzquiano, A. et al. Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex. Cell 185, 3770–3788.e27 (2022).
Camp, J. G. et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc. Natl Acad. Sci. USA 112, 15672–15677 (2015).
Ziffra, R. S. et al. Single-cell epigenomics reveals mechanisms of human cortical development. Nature 598, 205–213 (2021).
Deng, C. et al. Massively parallel characterization of regulatory elements in the developing human cortex. Science 384, eadh0559 (2024).
Fleck, J. S. et al. Resolving organoid brain region identities by mapping single-cell genomic data to reference atlases. Cell Stem Cell 28, 1148–1159.e8 (2021).
Sidhaye, J. et al. Integrated transcriptome and proteome analysis reveals posttranscriptional regulation of ribosomal genes in human brain organoids. eLife 12, e85135 (2023).
Trevino, A. E. et al. Chromatin accessibility dynamics in a model of human forebrain development. Science 367, eaay1645 (2020).
Zenk, F. et al. Single-cell epigenomic reconstruction of developmental trajectories from pluripotency in human neural organoid systems. Nat. Neurosci. 27, 1376–1386 (2024).
Wahle, P. et al. Multimodal spatiotemporal phenotyping of human retinal organoid development. Nat. Biotechnol. 41, 1765–1775 (2023).
Bai, Y. et al. Single-cell mapping of lipid metabolites using an infrared probe in human-derived model systems. Nat. Commun. 15, 350 (2024).
Saelens, W., Cannoodt, R., Todorov, H. & Saeys, Y. A comparison of single-cell trajectory inference methods. Nat. Biotechnol. 37, 547–554 (2019).
Coquand, L. et al. A cell fate decision map reveals abundant direct neurogenesis bypassing intermediate progenitors in the human developing neocortex. Nat. Cell Biol. 26, 698–709 (2024).
Frieda, K. L. et al. Synthetic recording and in situ readout of lineage information in single cells. Nature 541, 107–111 (2017).
Yao, Z. et al. A single-cell roadmap of lineage bifurcation in human ESC models of embryonic brain development. Cell Stem Cell 20, 120–134 (2017).
Alemany, A., Florescu, M., Baron, C. S., Peterson-Maduro, J. & van Oudenaarden, A. Whole-organism clone tracing using single-cell sequencing. Nature 556, 108–112 (2018).
Spanjaard, B. et al. Simultaneous lineage tracing and cell-type identification using CRISPR/Cas9-induced genetic scars. Nat. Biotechnol. 36, 469–473 (2018).
McKenna, A. & Gagnon, J. A. Recording development with single cell dynamic lineage tracing. Development 146, dev169730 (2019).
Raj, B. et al. Simultaneous single-cell profiling of lineages and cell types in the vertebrate brain. Nat. Biotechnol. 36, 442–450 (2018).
Lindenhofer, D. et al. Cerebral organoids display dynamic clonal growth and tunable tissue replenishment. Nat. Cell Biol. 26, 710–718 (2024).
Wagner, D. E. & Klein, A. M. Lineage tracing meets single-cell omics: opportunities and challenges. Nat. Rev. Genet. 21, 410–427 (2020).
He, Z. et al. Lineage recording in human cerebral organoids. Nat. Methods 19, 90–99 (2022).
Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K. & Sasai, Y. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 10, 537–550 (2015).
Sakaguchi, H. et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat. Commun. 6, 8896 (2015).
Jo, J. et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19, 248–257 (2016).
Trujillo, C. A. et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 558–569.e7 (2019).
Sharf, T. et al. Functional neuronal circuitry and oscillatory dynamics in human brain organoids. Nat. Commun. 13, 4403 (2022).
Gordon, A. et al. Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat. Neurosci. 24, 331–342 (2021).
Smits, L. M. et al. Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis. 5, 5 (2019).
Watanabe, M. et al. Self-organized cerebral organoids with human specific features predict effective drugs to combat Zika virus infection. Cell Rep. 21, 517–532 (2017).
Li, R. et al. Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease. Protein Cell 8, 823–833 (2017).
Xiang, Y. et al. hESC-derived thalamic organoids form reciprocal projections when fused with cortical organoids. Cell Stem Cell 24, 487–497.e7 (2019).
Birtele, M. et al. Single-cell transcriptional and functional analysis of dopaminergic neurons in organoid-like cultures derived from human fetal midbrain. Development 149, dev200504 (2022).
Landry, C. R. et al. Electrophysiological and morphological characterization of single neurons in intact human brain organoids. J. Neurosci. Methods 394, 109898 (2023).
Atamian, A. et al. Human cerebellar organoids with functional Purkinje cells. Cell Stem Cell 31, 39–51.e6 (2024).
Bardy, C. et al. Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology. Mol. Psychiatry 21, 1573–1588 (2016).
Cadwell, C. R. et al. Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat. Biotechnol. 34, 199–203 (2016).
Chen, B.-C. et al. Lattice light-sheet microscopy: imaging molecules to embryos at high spatiotemporal resolution. Science 346, 1257998 (2014).
Schöneberg, J. et al. 4D cell biology: big data image analytics and lattice light-sheet imaging reveal dynamics of clathrin-mediated endocytosis in stem cell-derived intestinal organoids. Mol. Biol. Cell 29, 2959–2968 (2018).
Lavagnino, Z. et al. 4D (x-y-z-t) imaging of thick biological samples by means of two-photon inverted selective plane illumination microscopy (2PE-iSPIM). Sci. Rep. 6, 23923 (2016).
Gonzalez, W. G., Zhang, H., Harutyunyan, A. & Lois, C. Persistence of neuronal representations through time and damage in the hippocampus. Science 365, 821–825 (2019).
Soscia, D. A. et al. A flexible 3-dimensional microelectrode array for in vitro brain models. Lab Chip 20, 901–911 (2020).
Buzsáki, G. Hippocampal sharp wave‐ripple: a cognitive biomarker for episodic memory and planning. Hippocampus 25, 1073–1188 (2015).
Le Floch, P. et al. Stretchable mesh nanoelectronics for three-dimensional single-cell chronic electrophysiology from developing brain organoids. Adv. Mater. 34, e2106829 (2022).
Shim, C. et al. Highly stretchable microelectrode array for free-form 3D neuronal tissue. In 33rd Int. Conf. Micro Electro Mech. Syst. (MEMS) 380–383 (IEEE, 2020).
Yang, X. et al. Kirigami electronics for long-term electrophysiological recording of human neural organoids and assembloids. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-02081-3 (2024).
Martinelli, E. et al. The e-flower: a hydrogel-actuated 3D MEA for brain spheroid electrophysiology. Sci. Adv. 10, eadp8054 (2024).
Kumar, S. et al. Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk. J. Neurodev. Disord. 11, 10 (2019).
Tsai, T. Y.-C. et al. An adhesion code ensures robust pattern formation during tissue morphogenesis. Science 370, 113–116 (2020).
Hergenreder, E. et al. Combined small molecule treatment accelerates maturation in human pluripotent stem cell-derived neurons. Nat. Biotechnol. 42, 1515–1525 (2024).
Urenda, J.-P., Del Dosso, A., Birtele, M. & Quadrato, G. Present and future modeling of human psychiatric connectopathies with brain organoids. Biol. Psychiatry 93, 606–615 (2023).
Horns, F. et al. Engineering RNA export for measurement and manipulation of living cells. Cell 186, 3642–3658.e32 (2023).
Farahany, N. A. et al. The ethics of experimenting with human brain tissue. Nature 556, 429–432 (2018).
Koch, C., Massimini, M., Boly, M. & Tononi, G. Neural correlates of consciousness: progress and problems. Nat. Rev. Neurosci. 17, 307–321 (2016).
Pașca, S. P. et al. A nomenclature consensus for nervous system organoids and assembloids. Nature 609, 907–910 (2022).
Ghosh, S., Nehme, R. & Barrett, L. E. Greater genetic diversity is needed in human pluripotent stem cell models. Nat. Commun. 13, 7301 (2022).
Schweitzer Jeffrey, S. et al. Personalized iPSC-derived dopamine progenitor cells for Parkinson’s disease. N. Engl. J. Med. 382, 1926–1932 (2020).
Parmar, M. & Björklund, A. From skin to brain: a Parkinson’s disease patient transplanted with his own cells. Cell Stem Cell 27, 8–10 (2020).
Takahashi, J. Preclinical evaluation of patient-derived cells shows promise for Parkinson’s disease. J. Clin. Invest. 130, 601–603 (2020).
Xu, H. et al. Targeted disruption of HLA genes via CRISPR–Cas9 generates iPSCs with enhanced immune compatibility. Cell Stem Cell 24, 566–578.e7 (2019).
Kitano, Y. et al. Generation of hypoimmunogenic induced pluripotent stem cells by CRISPR–Cas9 system and detailed evaluation for clinical application. Mol. Ther. Methods Clin. Dev. 26, 15–25 (2022).
Cloutier, M. et al. Preventing erosion of X-chromosome inactivation in human embryonic stem cells. Nat. Commun. 13, 2516 (2022).
Okamoto, I. et al. Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development. Nature 472, 370–374 (2011).
Sundar, S. J. et al. Three-dimensional organoid culture unveils resistance to clinical therapies in adult and pediatric glioblastoma. Transl. Oncol. 15, 101251 (2022).
Chen, X. et al. Antisense oligonucleotide therapeutic approach for Timothy syndrome. Nature 628, 818–825 (2024).
Harrison, R. G. Observations on the living developing nerve fiber. Proc. Soc. Exp. Biol. Med. 4, 140–143 (1906).
Wilson, H. V. On some phenomena of coalescence and regeneration in sponges. J. Exp. Zool. 5, 245–258 (1907).
Weiss, P. & Taylor, A. C. Reconstitution of complete organs from single-cell suspensions of chick embryos in advanced stages of differentiation. Proc. Natl Acad. Sci. USA 46, 1177–1185 (1960).
Pierce, G. B. Jr. & Verney, E. L. An in vitro and in vivo study of differentiation in teratocarcinomas. Cancer 14, 1017–1029 (1961).
Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Zhang, S. C., Wernig, M., Duncan, I. D., Brüstle, O. & Thomson, J. A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129–1133 (2001).
Elkabetz, Y. et al. Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes Dev. 22, 152–165 (2008).
Chambers, S. M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275–280 (2009).
Shi, Y., Kirwan, P. & Livesey, F. J. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat. Protoc. 7, 1836–1846 (2012).
Villalba, A., Götz, M. & Borrell, V. The regulation of cortical neurogenesis. Curr. Top. Dev. Biol. 142, 1–66 (2021).
Espuny-Camacho, I. et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77, 440–456 (2013).
Kirwan, P. et al. Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro. Development 142, 3178–3187 (2015).
Gaspard, N. et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455, 351–357 (2008).
Petersen, O. W., Rønnov-Jessen, L., Howlett, A. R. & Bissell, M. J. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc. Natl Acad. Sci. USA 89, 9064–9068 (1992).
Barcellos-Hoff, M. H., Aggeler, J., Ram, T. G. & Bissell, M. J. Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development 105, 223–235 (1989).
Watanabe, K. et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat. Neurosci. 8, 288–296 (2005).
Kadoshima, T. et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell–derived neocortex. Proc. Natl Acad. Sci. USA 110, 20284–20289 (2013).
Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011).
Nakano, T. et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785 (2012).
Nasu, M. et al. Robust formation and maintenance of continuous stratified cortical neuroepithelium by laminin-containing matrix in mouse ES cell culture. PLoS ONE 7, e53024 (2012).
Rosebrock, D. et al. Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells. Nat. Cell Biol. 24, 981–995 (2022).
Rigamonti, A. et al. Large-scale production of mature neurons from human pluripotent stem cells in a three-dimensional suspension culture system. Stem Cell Rep. 6, 993–1008 (2016).
Pellegrini, L. et al. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science 369, eaaz5626 (2020).
Huang, W.-K. et al. Generation of hypothalamic arcuate organoids from human induced pluripotent stem cells. Cell Stem Cell 28, 1657–1670.e10 (2021).
Kuwahara, A. et al. Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue. Nat. Commun. 6, 6286 (2015).
Fligor, C. M. et al. Three-dimensional retinal organoids facilitate the investigation of retinal ganglion cell development, organization and neurite outgrowth from human pluripotent stem cells. Sci. Rep. 8, 14520 (2018).
Tieng, V. et al. Engineering of midbrain organoids containing long-lived dopaminergic neurons. Stem Cell Dev. 23, 1535–1547 (2014).
Kim, H. et al. Modeling G2019S-LRRK2 sporadic Parkinson’s disease in 3D midbrain organoids. Stem Cell Rep. 12, 518–531 (2019).
Mohamed, N.-V. et al. Midbrain organoids with an SNCA gene triplication model key features of synucleinopathy. Brain Commun. 3, fcab223 (2021).
Monzel, A. S. et al. Derivation of human midbrain-specific organoids from neuroepithelial stem cells. Stem Cell Rep. 8, 1144–1154 (2017).
Ogura, T., Sakaguchi, H., Miyamoto, S. & Takahashi, J. Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells. Development 145, dev162214 (2018).
Gribaudo, S. et al. Self-organizing models of human trunk organogenesis recapitulate spinal cord and spine co-morphogenesis. Nat. Biotechnol. 42, 1243–1253 (2023).
Lee, J.-H. et al. Production of human spinal-cord organoids recapitulating neural-tube morphogenesis. Nat. Biomed. Eng. 6, 435–448 (2022).
Velasco, S., Paulsen, B. & Arlotta, P. 3D brain organoids: studying brain development and disease outside the embryo. Annu. Rev. Neurosci. 43, 375–389 (2020).
Jiang, X. & Nardelli, J. Cellular and molecular introduction to brain development. Neurobiol. Dis. 92, 3 (2015).
Sasai, N., Kadoya, M. & Ong Lee Chen, A. Neural induction: historical views and application to pluripotent stem cells. Dev. Growth Differ. 63, 26–37 (2021).
Del Dosso, A., Urenda, J.-P., Nguyen, T. & Quadrato, G. Upgrading the physiological relevance of human brain organoids. Neuron 107, 1014–1028 (2020).
Lancaster, M. A. & Knoblich, J. A. Generation of cerebral organoids from human pluripotent stem cells. Nat. Protoc. 9, 2329–2340 (2014).
Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).
Watanabe, M. et al. TGFβ superfamily signaling regulates the state of human stem cell pluripotency and capacity to create well-structured telencephalic organoids. Stem Cell Rep. 17, 2220–2238 (2022).
ten Berge, D. et al. Wnt signaling mediates self-organization and axis formation in embryoid bodies. Cell Stem Cell 3, 508–518 (2008).
Pagliaro, A. et al. Temporal morphogen gradient-driven neural induction shapes single expanded neuroepithelium brain organoids with enhanced cortical identity. Nat. Commun. 14, 7361 (2023).
Suzuki, I. K. & Vanderhaeghen, P. Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells. Development 142, 3138–3150 (2015).
Martins-Costa, C. et al. Morphogenesis and development of human telencephalic organoids in the absence and presence of exogenous extracellular matrix. EMBO J. 42, e113213 (2023).
Birtele, M. et al. Single cell transcriptional and functional analysis of human dopamine neurons in 3D fetal ventral midbrain organoid like cultures. Development 149, dev200504 (2022).
Hendriks, D. et al. Human fetal brain self-organizes into long-term expanding organoids. Cell 187, 712–732.e38 (2024).
Zhang, Z., Wang, X., Park, S., Song, H. & Ming, G.-L. Development and application of brain region–specific organoids for investigating psychiatric disorders. Biol. Psychiatry 93, 594–605 (2023).
Bosone, C. et al. A polarized FGF8 source specifies frontotemporal signatures in spatially oriented cell populations of cortical assembloids. Nat. Methods 21, 2147–2159 (2024).
Sloan, S. A., Andersen, J., Pașca, A. M., Birey, F. & Pașca, S. P. Generation and assembly of human brain region-specific three-dimensional cultures. Nat. Protoc. 13, 2062–2085 (2018).
Roth, J. G. et al. Spatially controlled construction of assembloids using bioprinting. Nat. Commun. 14, 4346 (2023).
Cullen, D. K. et al. Bundled three-dimensional human axon tracts derived from brain organoids. iScience 21, 57–67 (2019).
Robles, D., Boreland, A., Pang, Z. & Zahn, J. A cerebral organoid connectivity apparatus to model neuronal tract circuitry. Micromachines 12, 1574 (2021).
Martins-Costa, C. et al. ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum. Cell Stem Cell 31, 866–885.e14 (2024).
Yip, J. K. et al. Extended culture and imaging of normal and regenerating adult zebrafish hearts in a fluidic device. Lab Chip 20, 274–284 (2020).
Huang, T. et al. Tracing neuronal circuits in transgenic animals by transneuronal control of transcription (TRACT). eLife 6, e32027 (2017).
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