Understanding etiology of human neurological and psychiatric diseases is challenging. Genomic changes, protracted development, and histological features unique to human brain development limit the disease aspects that can be investigated using model organisms. Hence, in order to study phenotypes associated with human brain development, function, and disease, it is necessary to use alternative experimental systems that are accessible, ethically justified, and replicate human context. Human pluripotent stem cell (hPSC)-derived brain organoids offer such a system, which recapitulates features of early human neurodevelopment in vitro, including the generation, proliferation, and differentiation of neural progenitors into neurons and glial cells and the complex interactions among the diverse, emergent cell types of the developing brain in three-dimensions (3-D). In recent years, numerous brain organoid protocols and related techniques have been developed to recapitulate aspects of embryonic and fetal brain development in a reproducible and predictable manner. Altogether, these different organoid technologies provide distinct bioassays to unravel novel, disease-associated phenotypes and mechanisms. In this review, we summarize how the diverse brain organoid methods can be utilized to enhance our understanding of brain disorders.
Brain organoids offer an in vitro approach to study aspects of human brain development and disease.
Diverse brain organoid techniques offer bioassays to investigate new phenotypes associated with human brain disorders that are difficult to study in monolayer cultures.
Brain organoids have been particularly useful to study phenomena and diseases associated with neural progenitor morphology, survival, proliferation, and differentiation.
Future brain organoid research needs to aim at later stages of neurodevelopment, linked with neuronal activity and connections, to unravel further disease-associated phenotypes.
Continued improvement of existing organoid protocols is required to generate standardized methods that recapitulate in vivo-like spatial diversity and complexity.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hu WF, Chahrour MH, Walsh CA. The diverse genetic landscape of neurodevelopmental disorders. Annu Rev Genom Hum Genet. 2014;15:195–213.
Silbereis JC, Pochareddy S, Zhu Y, Li M, Sestan N. The cellular and molecular landscapes of the developing human central nervous system. Neuron. 2016;89:248–68.
Leung C, Jia Z. Mouse genetic models of human brain disorders. Front Genet. 2016;7:40.
Zhao X, Bhattacharyya A. Human models are needed for studying human neurodevelopmental disorders. Am J Hum Genet. 2018;103:829–57.
Avior Y, Sagi I, Benvenisty N. Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol. 2016;17:170–82.
Hotta A, Yamanaka S. From genomics to gene therapy: induced pluripotent stem cells meet genome editing. Annu Rev Genet. 2015;49:47–70.
Sterneckert JL, Reinhardt P, Schöler HR. Investigating human disease using stem cell models. Nat Rev Genet. 2014;15:625–39.
Itskovitz-Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, Amit M, et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med. 2000;6:88–95.
Watanabe K, Ueno M, Kamiya D, Nishiyama A, Matsumura M, Wataya T, et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol. 2007;25:681–6.
Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Stem Cell. 2008;3:519–32.
Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Stem Cell. 2012;10:771–85.
Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345:1247125.
Pașca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat methods. 2015;12:671–8.
Lancaster MA, Renner M, Martin C-A, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–9.
Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016;165:1238–54.
Renner M, Lancaster MA, Bian S, Choi H, Ku T, Peer A, et al. Self-organized developmental patterning and differentiation in cerebral organoids. EMBO J. 2017;36:1316–29.
Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Bräuninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci USA. 2015;112:15672–7.
Luo C, Lancaster MA, Castanon R, Nery JR, Knoblich JA, Ecker JR. Cerebral organoids recapitulate epigenomic signatures of the human fetal. Brain Cell Rep. 2016;17:3369–84.
Birey F, Andersen J, Makinson CD, Islam S, Wei W, Huber N, et al. Assembly of functionally integrated human forebrain spheroids. Nature. 2017;545:54–9.
Quadrato G, Nguyen T, Macosko EZ, Sherwood JL, Yang SM, Berger DR, et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature. 2017;545:48–53.
Yoon S-J, Elahi LS, Pașca AM, Marton RM, Gordon A, Revah O, et al. Reliability of human cortical organoid generation. Nat methods. 2018;16:75–78.
Giandomenico SL, Mierau SB, Gibbons GM, Wenger LMD, Masullo L, Sit T, et al. Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output. Nat Neurosci. 2019;22:669–79.
Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G, et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 2019;570:523–7.
Kanton S, Boyle MJ, He Z, Santel M, Weigert A, Sanchís-Calleja F, et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature. 2019;574:418–22.
Amiri A, Coppola G, Scuderi S, Wu F, Roychowdhury T, Liu F et al. Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science. 2018;362. https://doi.org/10.1126/science.aat6720.
Trevino AE, Sinnott-Armstrong N, Andersen J, Yoon S-J, Huber N, Pritchard JK, et al. Chromatin accessibility dynamics in a model of human forebrain development. Science. 2020;367:eaay1645.
Trujillo CA, Gao R, Negraes PD, Gu J, Buchanan J, Preissl S, et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Stem Cell. 2019;25:558–69.e7.
Madhavan M, Nevin ZS, Shick HE, Garrison E, Clarkson-Paredes C, Karl M, et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat Methods. 2018;110:20284.
Benito-Kwiecinski S, Lancaster MA. Brain organoids: human neurodevelopment in a dish. Cold Spring Harb Perspect Biol. 2019. https://doi.org/10.1101/cshperspect.a035709.
Simian M, Bissell MJ. Organoids: a historical perspective of thinking in three dimensions. J Cell Biol. 2016;216:31–40.
Qian X, Song H, Ming G-L. Brain organoids: advances, applications and challenges. Development. 2019;146:dev166074–12.
Heide M, Huttner WB, Mora-Bermúdez F. Brain organoids as models to study human neocortex development and evolution. Curr Opin Cell Biol. 2018;55:8–16.
Sullivan PF, Daly MJ, O’Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012;13:537–51.
Sullivan PF, Geschwind DH. Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders. Cell. 2019;177:162–83.
Li M, Santpere G, Imamura Kawasawa Y, Evgrafov OV, Gulden FO, Pochareddy S, et al. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science. 2018;362. https://doi.org/10.1126/science.aat7615.
Reilly SK, Noonan JP. Evolution of gene regulation in humans. Annu Rev Genom Hum Genet. 2016;17:45–67.
Doan RN, Shin T, Walsh CA. Evolutionary changes in transcriptional regulation: insights into human behavior and neurological conditions. Annu Rev Neurosci. 2018;41:185–206.
Heide M, Long KR, Huttner WB. Novel gene function and regulation in neocortex expansion. Curr Opin Cell Biol. 2017;49:22–30.
Florio M, Borrell V, Huttner WB. Human-specific genomic signatures of neocortical expansion. Curr Opin Neurobiol. 2017;42:33–44.
Franchini LF, Pollard KS. Human evolution: the non-coding revolution. BMC Biol. 2017;15:89.
Reilly SK, Yin J, Ayoub AE, Emera D, Leng J, Cotney J, et al. Evolutionary genomics. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science. 2015;347:1155–9.
Capra JA, Erwin GD, McKinsey G, Rubenstein JL, Pollard KS. Many human accelerated regions are developmental enhancers. Philos Trans R Soc Lond Ser B. 2013;368:20130025.
Doan RN, Bae BI, Cubelos B, Chang C, Hossain AA, Al-Saad S, et al. Mutations in human accelerated regions disrupt cognition and social behavior. Cell. 2016;167:341–54 e12.
Antonarakis SE. Down syndrome and the complexity of genome dosage imbalance. Nat Rev Genet. 2017;18:147–63.
Haydar TF, Reeves RH. Trisomy 21 and early brain development. Trends Neurosci. 2012;35:81–91.
Xu R, Brawner AT, Li S, Liu J-J, Kim H, Xue H, et al. OLIG2 drives abnormal neurodevelopmental phenotypes in human iPSC-based organoid and chimeric mouse models of Down syndrome. Stem Cell. 2019;24:908–26.e8.
Toma K, Wang T-C, Hanashima C. Encoding and decoding time in neural development. Dev Growth Differ. 2016;58:59–72.
Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell. 2015;162:375–90.
Schmitt A, Malchow B, Hasan A, Falkai P. The impact of environmental factors in severe psychiatric disorders. Front Neurosci. 2014;8. https://doi.org/10.3389/fnins.2014.00019.
Lee C-T, Chen J, Kindberg AA, Bendriem RM, Spivak CE, Williams MP, et al. CYP3A5 mediates effects of cocaine on human neocorticogenesis: studies using an in vitro 3D self-organized hPSC model with a single cortex-like unit. Neuropsychopharmacol. 2017;42:774–84.
Wang Y, Wang L, Zhu Y, Qin J. Human brain organoid-on-a-chip to model prenatal nicotine exposure. Lab Chip. 2018;18:851–60.
Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, 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. 2013;110:20284–9.
Muguruma K, Sasai Y. In vitro recapitulation of neural development using embryonic stem cells: From neurogenesis to histogenesis. Dev Growth Differ. 2012;54:349–57.
Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014;9:2329–40.
Klaus J, Kanton S, Kyrousi C, Ayo-Martin AC, Di Giaimo R, Riesenberg S, et al. Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. Nat Med. 2019;25:561–8.
Tanaka Y, Cakir B, Xiang Y, Sullivan GJ, Park I-H. Synthetic analyses of single-cell transcriptomes from multiple brain organoids and fetal brain. Cell Rep. 2020;30:1682–9.e3.
Suzuki IK, Vanderhaeghen P. Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells. Development. 2015;142:3138–50.
Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275–80.
Xiang Y, Tanaka Y, Cakir B, Patterson B, Kim K-Y, Sun P, et al. hESC-derived thalamic organoids form reciprocal projections when fused with cortical organoids. Stem Cell. 2019;24:487–97.e7.
Qian X, Jacob F, Song MM, Nguyen HN, Song H, Ming G-L. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc. 2018;13:565–80.
Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran H-D, Göke J, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell. 2016;19:248–57.
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. 2015;10:537–50.
Lancaster MA, Corsini NS, Wolfinger S, Gustafson EH, Phillips AW, Burkard TR, et al. Guided self-organization and cortical plate formation in human brain organoids. Nat Biotechnol. 2017;35:659–66.
Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M, et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun. 2015;6:8896–11.
Lupo G, Harris WA, Lewis KE. Mechanisms of ventral patterning in the vertebrate nervous system. Nat Rev Neurosci. 2006;7:103–14.
Bagley JA, Reumann D, Bian S, Levi-Strauss J, Knoblich JA. Fused cerebral organoids model interactions between brain regions. Nat Methods. 2017;14:743–51.
Xiang Y, Tanaka Y, Patterson B, Kang YJ, Govindaiah G, Roselaar N, et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell. 2017;21:383–98 e7.
Molnár Z, Clowry GJ, Šestan N, Alzu’bi A, Bakken T, Hevner RF, et al. New insights into the development of the human cerebral cortex. J Anat. 2018;235:432–51.
Clowry GJ, Alzu’bi A, Harkin LF, Sarma S, Kerwin J, Lindsay SJ. Charting the protomap of the human telencephalon. Semin Cell Dev Biol. 2018;76:3–14.
Smaers JB, Gómez-Robles A, Parks AN, Sherwood CC. Exceptional evolutionary expansion of prefrontal cortex in great apes and humans. Curr Biol. 2017;27:714–20.
Birnbaum R, Weinberger DR. Genetic insights into the neurodevelopmental origins of schizophrenia. Nat Rev Neurosci. 2017;18:727–40.
Gamo NJ, Arnsten AFT. Molecular modulation of prefrontal cortex: rational development of treatments for psychiatric disorders. Behav Neurosci. 2011;125:282–96.
Pollen AA, Bhaduri A, Andrews MG, Nowakowski TJ, Meyerson OS, Mostajo-Radji MA, et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell. 2019;176:743–56.e17.
Bhaduri A, Andrews MG, Mancia Leon W, Jung D, Shin D, Allen D, et al. Cell stress in cortical organoids impairs molecular subtype specification. Nature. 2020;110:20284–33.
Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci. 2005;28:57–87.
Kim H, Park HJ, Choi H, Chang Y, Park H, Shin J, et al. Modeling G2019S-LRRK2 sporadic Parkinson’s disease in 3D midbrain organoids. Stem Cell Rep. 2019;12:518–31.
Smits LM, Reinhardt L, Reinhardt P, Glatza M, Monzel AS, Stanslowsky N, et al. Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis. 2019;5:5–8.
Silva CG, Peyre E, Nguyen L. Cell migration promotes dynamic cellular interactions to control cerebral cortex morphogenesis. Nat Rev Neurosci. 2019;20:318–29.
López-Bendito G, Molnár Z. Thalamocortical development: how are we going to get there? Nat Rev Neurosci. 2003;4:276–89.
Ross ME, Walsh CA. Human brain malformations and their lessons for neuronal migration. Annu Rev Neurosci. 2001;24:1041–70.
Engle EC. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol. 2010;2:a001784.
Cederquist GY, Asciolla JJ, Tchieu J, Walsh RM, Cornacchia D, Resh MD, et al. Specification of positional identity in forebrain organoids. Nat Biotechnol. 2019;37:436–44.
Beggs S, Salter MW. SnapShot: microglia in disease. Cell. 2016;165:1294–1294.e1.
Ormel PR, Vieira de Sá R, van Bodegraven EJ, Karst H, Harschnitz O, Sneeboer MAM, et al. Microglia innately develop within cerebral organoids. Nat Commun. 2018;9:4167–14.
Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron. 2017;94:278–93.e9.
Song L, Yuan X, Jones Z, Vied C, Miao Y, Marzano M, et al. Functionalization of brain region-specific spheroids with isogenic microglia-like cells. Sci Rep. 2019;9:11055–18.
Lin Y-T, Seo J, Gao F, Feldman HM, Wen H-L, Penney J, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98:1141–54.e7.
Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013;19:1584–96.
Mansour AA, Gonçalves JT, Bloyd CW, Li H, Fernandes S, Quang D, et al. An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol. 2018;36:432–41.
Cakir B, Xiang Y, Tanaka Y, Kural MH, Parent M, Kang Y-J, et al. Engineering of human brain organoids with a functional vascular-like system. Nat Methods. 2019;16:1169–75.
Shi Y, Sun L, Liu J, Zhong S, Wang M, Li R, et al. Vascularized human cortical organoids model cortical development in vivo. 2019. https://doi.org/10.1101/682104.
Linkous A, Balamatsias D, Snuderl M, Edwards L, Miyaguchi K, Milner T, et al. Modeling patient-derived glioblastoma with cerebral organoids. Cell Rep. 2019;26:3203–11.e5.
Bhaduri A, Di Lullo E, Jung D, Müller S, Crouch EE, Espinosa CS, et al. Outer radial glia-like cancer stem cells contribute to heterogeneity of glioblastoma. Stem Cell. 2020;26:48–63.e6.
Amin ND, Paşca SP. Building models of brain disorders with three-dimensional organoids. Neuron. 2018;100:389–405.
Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017;18:573–84.
Sun T, Hevner RF. Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat Rev Neurosci. 2014;15:217–32.
Taverna E, Götz M, Huttner WB. The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Annu Rev Cell Dev Biol. 2014;30:465–502.
Florio M, Huttner WB. Neural progenitors, neurogenesis and the evolution of the neocortex. Development. 2014;141:2182–94.
Woods CG, Bond J, Enard W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. AJHG. 2005;76:717–28.
Jayaraman D, Bae B-I, Walsh CA. The genetics of primary microcephaly. Annu Rev Genom Hum Genet. 2018;19:177–200.
Alkuraya FS, Cai X, Emery C, Mochida GH, Al-Dosari MS, Felie JM, et al. Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]. Am J Hum Genet. 2011;88:536–47.
Feng Y, Walsh CA. Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron. 2004;44:279–93.
Zhang W, Yang S-L, Yang M, Herrlinger S, Shao Q, Collar JL, et al. Modeling microcephaly with cerebral organoids reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly in neural progenitors. Nat Commun. 2019;10:2612–14.
Silasi M, Cardenas I, Kwon J-Y, Racicot K, Aldo P, Mor G. Viral infections during pregnancy. Am J Reprod Immunol. 2015;73:199–213.
Garcez PP, Loiola EC, Madeiro da Costa R, Higa LM, Trindade P, Delvecchio R, et al. Zika virus impairs growth in human neurospheres and brain organoids. Science. 2016;352:816–8.
Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JLM, Guimarães KP, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534:267–71.
Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Stem Cell. 2016;19:258–65.
Xu Y-P, Qiu Y, Zhang B, Chen G, Chen Q, Wang M, et al. Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids. Cell Res. 2019;29:265–73.
Watanabe M, Buth JE, Vishlaghi N, la Torre-Ubieta de L, Taxidis J, Khakh BS, et al. Self-organized cerebral organoids with human- specific features predict effective drugs to combat Zika virus. Infect Cell Rep. 2017;21:517–32.
Zhou T, Tan L, Cederquist GY, Fan Y, Hartley BJ, Mukherjee S, et al. High-content screening in hPSC-neural progenitors identifies drug candidates that inhibit Zika virus infection in fetal-like organoids and adult. Brain Stem Cell. 2017;21:274–83.e5.
Butler MG. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005;42:318–21.
Marchese M, Conti V, Valvo G, Moro F, Muratori F, Tancredi R, et al. Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening. BMC Med Genet. 2014;15:26–7.
Li Y, Muffat J, Omer A, Bosch I, Lancaster MA, Sur M, et al. Induction of expansion and folding in human cerebral organoids. Stem Cell. 2017;20:385–96.e3.
Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina ME, Ordóñez-Morán P, et al. Designer matrices for intestinal stem cell and organoid culture. Nature. 2016;539:560–4.
Cruz-Acuña R, Quirós M, Farkas AE, Dedhia PH, Huang S, Siuda D, et al. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat Cell Biol. 2017;19:1326–35.
Qian X, Su Y, Adam CD, Deutschmann AU, Pather SR, Goldberg EM, et al. Sliced human cortical organoids for modeling distinct cortical layer formation. Cell Stem Cell. 2020. https://doi.org/10.1016/j.stem.2020.02.002.
Brassard JA, Lutolf MP. Engineering stem cell self-organization to build better organoids. Cell Stem Cell. 2019;24:860–76.
Ghatak S, Dolatabadi N, Trudler D, Zhang X, Wu Y, Mohata M, et al. Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls. eLife. 2019;8:1567–22.
Sun AX, Yuan Q, Fukuda M, Yu W, Yan H, Lim GGY, et al. Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science. 2019;366:1486–92.
Shalem O, Sanjana NE, Zhang F. High-throughput functional genomics using CRISPR-Cas9. Nat Rev Genet. 2015;16:299–311.
Camp JG, Platt R, Treutlein B. Mapping human cell phenotypes to genotypes with single-cell genomics. Science. 2019;365:1401–5.
Almanza A, Carlesso A, Chintha C, Creedican S, Doultsinos D, Leuzzi B, et al. Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. FEBS J. 2018;286:241–78.
Li R, Sun L, Fang A, Li P, Wu Q, Wang X. Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease. Protein Cell. 2017;8:823–33.
Gabriel E, Wason A, Ramani A, Gooi LM, Keller P, Pozniakovsky A, et al. CPAPpromotes timely cilium disassembly to maintain neural progenitor pool. EMBO J. 2016;35:803–19.
Thomas CA, Tejwani L, Trujillo CA, Negraes PD, Herai RH, Mesci P, et al. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Stem Cell. 2017;21:319–31.e8.
Allende ML, Cook EK, Larman BC, Nugent A, Brady JM, Golebiowski D, et al. Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation. J Lipid Res. 2018;59:550–63.
Bershteyn M, Nowakowski TJ, Pollen AA, Di Lullo E, Nene A, Wynshaw-Boris A, et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial. Glia Stem Cell. 2017;20:435–49.e4.
Iefremova V, Manikakis G, Krefft O, Jabali A, Weynans K, Wilkens R, et al. An organoid-based model of cortical development identifies non-cell-autonomous defects in wnt signaling contributing to Miller-Dieker Syndrome. Cell Rep. 2017;19:50–59.
Bian S, Repic M, Guo Z, Kavirayani A, Burkard T, Bagley JA, et al. Genetically engineered cerebral organoids model brain tumor formation. Nat Methods. 2018;15:631–9.
Ogawa J, Pao GM, Shokhirev MN, Verma IM. Glioblastoma model using human cerebral organoids. Cell Rep. 2018;23:1220–9.
Schafer ST, Paquola ACM, Stern S, Gosselin D, Ku M, Pena M, et al. Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. Nat Neurosci. 2019;22:243–55.
Mellios N, Feldman DA, Sheridan SD, Ip JPK, Kwok S, Amoah SK, et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry. 2017;23:1051–65.
Raja WK, Mungenast AE, Lin Y-T, Ko T, Abdurrob F, Seo J, et al. Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS ONE. 2016;11:e0161969–18.
Gonzalez C, Armijo E, Bravo-Alegria J, Becerra-Calixto A, Mays CE, Soto C. Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry. 2018;23:2363–74.
Seo J, Kritskiy O, Watson LA, Barker SJ, Dey D, Raja WK, et al. Inhibition of p25/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia. J Neurosci. 2017;37:9917–24.
Srikanth P, Lagomarsino VN, Muratore CR, Ryu SC, He A, Taylor WM, et al. Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids. Transl Psychiatry. 2018;8:77–14.
Ye F, Kang E, Yu C, Qian X, Jacob F, Yu C, et al. DISC1 regulates neurogenesis via modulating kinetochore attachment of Ndel1/Nde1 during mitosis. Neuron. 2017;96:1041–54 e5.
Blair JD, Hockemeyer D, Bateup HS. Genetically engineered human cortical spheroid models of tuberous sclerosis. Nat Med. 2018;24:1568–78.
Pașca AM, Park J-Y, Shin H-W, Qi Q, Revah O, Krasnoff R, et al. Human 3D cellular model of hypoxic brain injury of prematurity. Nat Med. 2019;25:784–91.
Boisvert EM, Means RE, Michaud M, Madri JA, Katz SG. Minocycline mitigates the effect of neonatal hypoxic insult on human brain organoids. Cell Death Dis. 2019;10:325–11.
Paşca SP. Building three-dimensional human brain organoids. Nat Neurosci. 2018. https://doi.org/10.1038/s41593-018-0107-3.
We would like to thank the Knoblich lab members for their feedback on the manuscript. We apologize to the authors, whose work could not be cited due to the space limitations. Work in the Knoblich laboratory is supported by the Österreichischen Akademie der Wissenschaften, the Austrian Science Fund (Z_153_B09), and an advanced grant from the European Research Council under the European Union’s Horizon 2020 research and innovation program (GA 695642). JS was supported by EMBO long term fellowship (EMBO ALTF 794-2018).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by F. Pentimalli
About this article
Cite this article
Sidhaye, J., Knoblich, J.A. Brain organoids: an ensemble of bioassays to investigate human neurodevelopment and disease. Cell Death Differ 28, 52–67 (2021). https://doi.org/10.1038/s41418-020-0566-4
Balancing serendipity and reproducibility: Pluripotent stem cells as experimental systems for intellectual and developmental disorders
Stem Cell Reports (2021)
Nanogold induces anti-inflammation against oxidative stress induced in human neural stem cells exposed to amyloid-beta peptide
Neurochemistry International (2021)
Expert Opinion on Therapeutic Targets (2021)
Cell-to-Cell Adhesion and Neurogenesis in Human Cortical Development: A Study Comparing 2D Monolayers with 3D Organoid Cultures
Stem Cell Reports (2021)
The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair
International Journal of Molecular Sciences (2021)