International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
권호 표지
DOI QR코드

DOI QR Code

Guidelines for Manufacturing and Application of Organoids: Brain

  • Taehwan Kwak (Next & Bio Inc.) ;
  • Si-Hyung Park (Department of Anatomy, Korea University College of Medicine) ;
  • Siyoung Lee (Next & Bio Inc.) ;
  • Yujeong Shin (Next & Bio Inc.) ;
  • Ki-Jun Yoon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Seung-Woo Cho (Organoid Standards Initiative) ;
  • Jong-Chan Park (Organoid Standards Initiative) ;
  • Seung-Ho Yang (Organoid Standards Initiative) ;
  • Heeyeong Cho (Organoid Standards Initiative) ;
  • Heh-In Im (Organoid Standards Initiative) ;
  • Sun-Ju Ahn (Organoid Standards Initiative) ;
  • Woong Sun (Department of Anatomy, Korea University College of Medicine) ;
  • Ji Hun Yang (Next & Bio Inc.)
  • Received : 2024.04.24
  • Accepted : 2024.05.09
  • Published : 2024.05.30
Download PDF
⟨ Previous Next ⟩

Abstract

This study offers a comprehensive overview of brain organoids for researchers. It combines expert opinions with technical summaries on organoid definitions, characteristics, culture methods, and quality control. This approach aims to enhance the utilization of brain organoids in research. Brain organoids, as three-dimensional human cell models mimicking the nervous system, hold immense promise for studying the human brain. They offer advantages over traditional methods, replicating anatomical structures, physiological features, and complex neuronal networks. Additionally, brain organoids can model nervous system development and interactions between cell types and the microenvironment. By providing a foundation for utilizing the most human-relevant tissue models, this work empowers researchers to overcome limitations of two-dimensional cultures and conduct advanced disease modeling research.

Keywords

Acknowledgement

This work was supported by a grant (23212MFDS265) from the Ministry of Food and Drug Safety in 2023.

References

  1. Vieira de Sa R, Canizares Luna M, Pasterkamp RJ. Advances in central nervous system organoids: a focus on organoidbased models for motor neuron disease. Tissue Eng Part C Methods 2021;27:213-224
  2. Pacitti D, Privolizzi R, Bax BE. Organs to cells and cells to organoids: the evolution of in vitro central nervous system modelling. Front Cell Neurosci 2019;13:129
  3. Costamagna G, Comi GP, Corti S. Advancing drug discovery for neurological disorders using iPSC-derived neural organoids. Int J Mol Sci 2021;22:2659
  4. Giorgi C, Lombardozzi G, Ammannito F, et al. Brain organoids: a game-changer for drug testing. Pharmaceutics 2024;16:443
  5. Hong YJ, Lee SB, Choi J, Yoon SH, Do JT. A simple method for generating cerebral organoids from human pluripotent stem cells. Int J Stem Cells 2022;15:95-103
  6. Kim J. Lo and behold, the lab-grown organs have arrived! Int J Stem Cells 2022;15:1-2
  7. Chukwurah E, Osmundsen A, Davis SW, Lizarraga SB. All together now: modeling the interaction of neural with nonneural systems using organoid models. Front Neurosci 2019;13:582
  8. Makrygianni EA, Chrousos GP. From brain organoids to networking assembloids: implications for neuroendocrinology and stress medicine. Front Physiol 2021;12:621970
  9. Bhattacharya A, Choi WWY, Muffat J, Li Y. Modeling developmental brain diseases using human pluripotent stem cells-derived brain organoids - progress and perspective. J Mol Biol 2022;434:167386
  10. Wang H. Modeling neurological diseases with human brain organoids. Front Synaptic Neurosci 2018;10:15
  11. Wray S. Modelling neurodegenerative disease using brain organoids. Semin Cell Dev Biol 2021;111:60-66
  12. Salick MR, Lubeck E, Riesselman A, Kaykas A. The future of cerebral organoids in drug discovery. Semin Cell Dev Biol 2021;111:67-73
  13. Sun N, Meng X, Liu Y, Song D, Jiang C, Cai J. Applications of brain organoids in neurodevelopment and neurological diseases. J Biomed Sci 2021;28:30
  14. Tang XY, Wu S, Wang D, et al. Human organoids in basic research and clinical applications. Signal Transduct Target Ther 2022;7:168
  15. Grenier K, Kao J, Diamandis P. Three-dimensional modeling of human neurodegeneration: brain organoids coming of age. Mol Psychiatry 2020;25:254-274
  16. Susaimanickam PJ, Kiral FR, Park IH. Region specific brain organoids to study neurodevelopmental disorders. Int J Stem Cells 2022;15:26-40
  17. Yadav A, Seth B, Chaturvedi RK. Brain organoids: tiny mirrors of human neurodevelopment and neurological disorders. Neuroscientist 2021;27:388-426
  18. Muzio L, Consalez GG. Modeling human brain development with cerebral organoids. Stem Cell Res Ther 2013;4:154
  19. Qian X, Song H, Ming GL. Brain organoids: advances, applications and challenges. Development 2019;146:dev166074
  20. Zhao HH, Haddad G. Brain organoid protocols and limitations. Front Cell Neurosci 2024;18:1351734
  21. Kim SH, Chang MY. Application of human brain organoids-opportunities and challenges in modeling human brain development and neurodevelopmental diseases. Int J Mol Sci 2023;24:12528
  22. Zhou Z, Cong L, Cong X. Patient-derived organoids in precision medicine: drug screening, organoid-on-a-chip and living organoid biobank. Front Oncol 2021;11:762184
  23. Chen CC, Li HW, Wang YL, et al. Patient-derived tumor organoids as a platform of precision treatment for malignant brain tumors. Sci Rep 2022;12:16399
  24. Korhonen P, Malm T, White AR. 3D human brain cell models: new frontiers in disease understanding and drug discovery for neurodegenerative diseases. Neurochem Int 2018;120:191-199
  25. Liu S, He Y, Yin J, Zhu Q, Liao C, Jiang G. Neurotoxicities induced by micro/nanoplastics: a review focusing on the risks of neurological diseases. J Hazard Mater 2024;469:134054
  26. Casey S, Carter M, Looney AM, et al. Maternal mid-gestation cytokine dysregulation in mothers of children with autism spectrum disorder. J Autism Dev Disord 2022;52:3919-3932
  27. Jarmund AH, Giskeodegard GF, Ryssdal M, et al. Cytokine patterns in maternal serum from first trimester to term and beyond. Front Immunol 2021;12:752660
  28. Rash BG, Grove EA. Area and layer patterning in the developing cerebral cortex. Curr Opin Neurobiol 2006;16:25-34
  29. Berman NE, Johnson JK, Klein RM. Early generation of glia in the intermediate zone of the developing cerebral cortex. Brain Res Dev Brain Res 1997;101:149-164
  30. De Juan Romero C, Borrell V. Coevolution of radial glial cells and the cerebral cortex. Glia 2015;63:1303-1319
  31. Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature 2013;501:373-379
  32. Pasca AM, Sloan SA, Clarke LE, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 2015;12:671-678
  33. Eiraku M, Watanabe K, Matsuo-Takasaki M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 2008;3:519-532
  34. Huang WK, Wong SZH, Pather SR, et al. Generation of hypothalamic arcuate organoids from human induced pluripotent stem cells. Cell Stem Cell 2021;28:1657-1670.e10
  35. Matsumoto R, Suga H, Aoi T, et al. Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells. J Clin Invest 2020;130:641-654
  36. Nakano T, Ando S, Takata N, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 2012;10:771-785
  37. Pomeshchik Y, Klementieva O, Gil J, et al. Human iPSC-derived hippocampal spheroids: an innovative tool for stratifying Alzheimer disease patient-specific cellular phenotypes and developing therapies. Stem Cell Reports 2021;16:2838
  38. Ballabio C, Anderle M, Gianesello M, et al. Modeling medulloblastoma in vivo and with human cerebellar organoids. Nat Commun 2020;11:583
  39. Jo J, Xiao Y, Sun AX, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 2016;19:248-257
  40. Smits LM, Reinhardt L, Reinhardt P, et al. Modeling Parkinson's disease in midbrain-like organoids. NPJ Parkinsons Dis 2019;5:5
  41. Kim H, Xu R, Padmashri R, et al. Pluripotent stem cell-derived cerebral organoids reveal human oligodendrogenesis with dorsal and ventral origins. Stem Cell Reports 2019;12:890-905
  42. Mills RJ, Parker BL, Quaife-Ryan GA, et al. Drug screening in human PSC-cardiac organoids identifies pro-proliferative compounds acting via the mevalonate pathway. Cell Stem Cell 2019;24:895-907.e6
  43. Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013;499:481-484
  44. Takebe T, Enomura M, Yoshizawa E, et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell 2015;16:556-565
  45. Guan Y, Xu D, Garfin PM, et al. Human hepatic organoids for the analysis of human genetic diseases. JCI Insight 2017;2:e94954
  46. Takasato M, Er PX, Becroft M, et al. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat Cell Biol 2014;16:118-126
  47. 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;8:823-833
  48. Omer Javed A, Li Y, et al. Microcephaly modeling of kinetochore mutation reveals a brain-specific phenotype. Cell Rep 2018;25:368-382.e5
  49. Wang L, Li Z, Sievert D, et al. Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly. Nat Commun 2020;11:4038
  50. Cugola FR, Fernandes IR, Russo FB, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 2016;534:267-271
  51. Qian X, Nguyen HN, Song MM, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 2016;165:1238-1254
  52. Mariani J, Coppola G, Zhang P, et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 2015;162:375-390
  53. Wang P, Mokhtari R, Pedrosa E, et al. CRISPR/Cas9- mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells. Mol Autism 2017;8:11
  54. Hali S, Kim J, Kwak TH, Lee H, Shin CY, Han DW. Modelling monogenic autism spectrum disorder using mouse cortical organoids. Biochem Biophys Res Commun 2020;521:164-171
  55. Mellios N, Feldman DA, Sheridan SD, et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry 2018;23:1051-1065
  56. Xiang Y, Tanaka Y, Patterson B, et al. Dysregulation of BRD4 function underlies the functional abnormalities of MeCP2 mutant neurons. Mol Cell 2020;79:84-98.e9
  57. Gomes AR, Fernandes TG, Vaz SH, et al. Modeling Rett syndrome with human patient-specific forebrain organoids. Front Cell Dev Biol 2020;8:610427
  58. Xu R, Brawner AT, Li S, et al. OLIG2 drives abnormal neurodevelopmental phenotypes in human iPSC-based organoid and chimeric mouse models of Down syndrome. Cell Stem Cell 2019;24:908-926.e8
  59. Tang XY, Xu L, Wang J, et al. DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome. J Clin Invest 2021;131:e135763
  60. Jin M, Pomp O, Shinoda T, et al. Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics. Sci Rep 2017;7:39902
  61. Srikanth P, Lagomarsino VN, Muratore CR, et al. Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids. Transl Psychiatry 2018;8:77
  62. Yin J, VanDongen AM. Enhanced neuronal activity and asynchronous calcium transients revealed in a 3D organoid model of Alzheimer's disease. ACS Biomater Sci Eng 2021;7:254-264
  63. Zhao J, Fu Y, Yamazaki Y, et al. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids. Nat Commun 2020;11:5540
  64. Perez MJ, Ivanyuk D, Panagiotakopoulou V, et al. Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer's disease-like pathology in human cerebral organoids. Mol Psychiatry 2021;26:5733-5750
  65. Kwak TH, Kang JH, Hali S, et al. Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling. Stem Cells 2020;38:727-740
  66. Kim H, Park HJ, Choi H, et al. Modeling G2019S-LRRK2 sporadic Parkinson's disease in 3D midbrain organoids. Stem Cell Reports 2019;12:518-531
  67. Jo J, Yang L, Tran HD, et al. Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations. Ann Neurol 2021;90:490-505
  68. Quadrato G, Nguyen T, Macosko EZ, et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 2017;545:48-53
  69. Renner M, Lancaster MA, Bian S, et al. Self-organized developmental patterning and differentiation in cerebral organoids. EMBO J 2017;36:1316-1329
  70. Sloan SA, Darmanis S, Huber N, et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 2017;95:779-790.e6
  71. Marton RM, Miura Y, Sloan SA, et al. Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat Neurosci 2019;22:484-491
  72. Madhavan M, Nevin ZS, Shick HE, et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat Methods 2018;15:700-706
  73. Trujillo CA, Gao R, Negraes PD, et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 2019;25:558-569.e7
  74. Birey F, Andersen J, Makinson CD, et al. Assembly of functionally integrated human forebrain spheroids. Nature 2017;545:54-59
  75. Xiang Y, Tanaka Y, Patterson B, et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 2017; 21:383-398.e7
  76. Bagley JA, Reumann D, Bian S, Levi-Strauss J, Knoblich JA. Fused cerebral organoids model interactions between brain regions. Nat Methods 2017;14:743-751
  77. Lee JH, Shin H, Shaker MR, et al. Production of human spinal-cord organoids recapitulating neural-tube morphogenesis. Nat Biomed Eng 2022;6:435-448
  78. Cooper F, Gentsch GE, Mitter R, et al. Rostrocaudal patterning and neural crest differentiation of human pre-neural spinal cord progenitors in vitro. Stem Cell Reports 2022;17:894-910
  79. Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 2014;9:2329-2340
  80. Watanabe M, Buth JE, Vishlaghi N, et al. Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection. Cell Rep 2017;21:517-532
  81. Wickham J, Corna A, Schwarz N, et al. Human cerebrospinal fluid induces neuronal excitability changes in resected human neocortical and hippocampal brain slices. Front Neurosci 2020;14:283
  82. Hill CL, Stephens GJ. An introduction to patch clamp recording. Methods Mol Biol 2021;2188:1-19
  83. Passaro AP, Stice SL. Electrophysiological analysis of brain organoids: current approaches and advancements. Front Neurosci 2021;14:622137
  84. Schroter M, Wang C, Terrigno M, et al. Functional imaging of brain organoids using high-density microelectrode arrays. MRS Bull 2022;47:530-544
  85. Shin H, Jeong S, Lee JH, Sun W, Choi N, Cho IJ. 3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics. Nat Commun 2021;12:492
  86. Telias M, Ben-Yosef D. Neural stem cell replacement: a possible therapy for neurodevelopmental disorders? Neural Regen Res 2015;10:180-182
  87. Durens M, Nestor J, Williams M, et al. High-throughput screening of human induced pluripotent stem cell-derived brain organoids. J Neurosci Methods 2020;335:108627
  88. Huang Q, Tang B, Romero JC, et al. Shell microelectrode arrays (MEAs) for brain organoids. Sci Adv 2022;8:eabq5031
  89. Nickels SL, Modamio J, Mendes-Pinheiro B, Monzel AS, Betsou F, Schwamborn JC. Reproducible generation of human midbrain organoids for in vitro modeling of Parkinson's disease. Stem Cell Res 2020;46:101870
  90. Anand P, Stahel VP. Review the safety of Covid-19 mRNA vaccines: a review. Patient Saf Surg 2021;15:20
  91. Brussow H. COVID-19: vaccination problems. Environ Microbiol 2021;23:2878-2890