Human Brain Organoids in the Preclinical Phase of Drug Development for Migraine
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Parisa Gazerani
http://orcid.org/0000-0003-0109-3600
http://orcid.org/0000-0003-0109-3600
Abstract
Developing drugs for brain disorders poses significant hurdles. These challenges stem from the scarcity of optimal models for preclinical drug testing and the often observed lack of translation from preclinical to human clinical trials. Further complexity arises from the specific targeting required in many brain disorders, with drug delivery often impeded by the necessity to cross the blood-brain barrier (BBB). As such, the search for novel and efficient platforms for preclinical drug development is a vibrant area of research. In acknowledgment of the limitations of animal tests - such as the lack of translation owing to species differences - and in alignment with the principles of reduction, refinement, and replacement (3Rs), the scientific community is moving towards promoting animal-free drug development plans. In this context, human brain organoids are rapidly emerging as potential alternatives to traditional methods. These early-stage in vitro models, mirroring in vivo complexities, hold great promise for preclinical drug testing for brain disorders. Stable organoid phenotypes and the uncovering of disease-specific features could soon elevate them to a valuable strategy in pharmaceutical testing for a range of brain disorders. Recent advancements in assay-ready organoid platforms and microfluidic chips present considerable potential for the application of human brain organoids in drug development. This commentary briefly discusses the generation of human brain organoids and their application in drug development with existing examples, focusing on their potential use in preclinical drug development for migraine, a prevalent, complex, and disabling brain disorder. The associated challenges and opportunities will also be outlined.
Keywords:
Organoids, Brain organoids, Human brain organoids, Migraine, Drug development, Preclinical phase, Drug screening
Article Details
How to Cite
GAZERANI, Parisa.
Human Brain Organoids in the Preclinical Phase of Drug Development for Migraine.
Medical Research Archives, [S.l.], v. 12, n. 2, feb. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5117>. Date accessed: 23 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i2.5117.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Kim SH, Chang MY. Application of Human Brain Organoids-Opportunities and Challenges in Modeling Human Brain Development and Neurodevelopmental Diseases. Int J Mol Sci. Aug 7 2023;24(15)doi:10.3390/ijms241512528
2. Ma C, Seong H, Li X, Yu X, Xu S, Li Y. Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening. Stem Cells Int. 2022;2022:2150680. doi:10.1155/2022/2150680
3. Zhou JQ, Zeng LH, Li CT, et al. Brain organoids are new tool for drug screening of neurological diseases. Neural Regen Res. Sep 2023;18(9):1884-1889. doi:10.4103/1673-5374.367983
4. Xu J, Wen Z. Brain Organoids: Studying Human Brain Development and Diseases in a Dish. Stem Cells Int. 2021;2021:5902824. doi:10.1155/2021/5902824
5. Li Y, Zeng P-M, Wu J, Luo Z-G. Advances and Applications of Brain Organoids. Neuroscience Bulletin. 2023/11/01 2023;39(11):1703-1716. doi:10.1007/s12264-023-01065-2
6. Wang H. Modeling Neurological Diseases With Human Brain Organoids. Front Synaptic Neurosci. 2018;10:15. doi:10.3389/fnsyn.2018.00015
7. Feigin VL, Vos T, Nichols E, et al. The global burden of neurological disorders: translating evidence into policy. Lancet Neurol. Mar 2020;19(3):255-265. doi:10.1016/s1474-4422(19)30411-9
8. 8. Owolabi MO, Leonardi M, Bassetti C, et al. Global synergistic actions to improve brain health for human development. Nature Reviews Neurology. 2023/06/01 2023;19(6):371-383. doi:10.1038/s41582-023-00808-z
9. Wareham LK, Liddelow SA, Temple S, et al. Solving neurodegeneration: common mechanisms and strategies for new treatments. Molecular Neurodegeneration. 2022/03/21 2022;17(1):23. doi:10.1186/s13024-022-00524-0
10. Ningrum DNA, Kung WM. Challenges and Perspectives of Neurological Disorders. Brain Sci. Apr 18 2023;13(4)doi:10.3390/brainsci13040676
11. Markou A, Chiamulera C, Geyer MA, Tricklebank M, Steckler T. Removing Obstacles in Neuroscience Drug Discovery: The Future Path for Animal Models. Neuropsychopharmacology. 2009/01/01 2009;34(1):74-89. doi:10.1038/npp.2008.173
12. Dawson TM, Golde TE, Lagier-Tourenne C. Animal models of neurodegenerative diseases. Nat Neurosci. Oct 2018;21(10):1370-1379. doi:10.1038/s41593-018-0236-8
13. Qian L, Tcw J. Human iPSC-Based Modeling of Central Nerve System Disorders for Drug Discovery. International Journal of Molecular Sciences. 2021;22(3). doi:10.3390/ijms22031203
14. Gazerani P. Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development. Int J Mol Sci. Feb 4 2023;24(4)doi:10.3390/ijms24043113
15. Chhibber T, Bagchi S, Lahooti B, et al. CNS organoids: an innovative tool for neurological disease modeling and drug neurotoxicity screening. Drug Discov Today. Feb 2020;25(2):456-465. doi:10.1016/j.drudis.2019.11.010
16. Cherskov A, Sestan N. A screen of brain organoids to study neurodevelopmental disease. Nature. Jan 2021;589(7840):24-25. doi:10.1038/d41586-020-03636-z
17. Lancaster MA, Renner M, Martin C-A, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013/09/01 2013;501(7467):373-379. doi:10.1038/nature12517
18. Clevers H. Modeling Development and Disease with Organoids. Cell. Jun 16 2016;165(7):1586-1597. doi:10.1016/j.cell.2016.05.082
19. Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. Oct 2017;18(10):573-584. doi:10.1038/nrn.2017.107
20. Qian X, Song H, Ming GL. Brain organoids: advances, applications and challenges. Development. Apr 16 2019;146(8)doi:10.1242/dev.166074
21. Sun N, Meng X, Liu Y, Song D, Jiang C, Cai J. Applications of brain organoids in neurodevelopment and neurological diseases. Journal of Biomedical Science. 2021/04/22 2021;28(1):30. doi:10.1186/s12929-021-00728-4
22. Castiglione H, Vigneron PA, Baquerre C, Yates F, Rontard J, Honegger T. Human Brain Organoids-on-Chip: Advances, Challenges, and Perspectives for Preclinical Applications. Pharmaceutics. Oct 26 2022;14(11)doi:10.3390/pharmaceutics14112301
23. Smirnova L, Morales Pantoja IE, Hartung T. Organoid intelligence (OI) - The ultimate functionality of a brain microphysiological system. Altex. 2023;40(2):191-203. doi:10.14573/altex.2303261
24. Marsee A, Roos FJM, Verstegen MMA, et al. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids. Cell Stem Cell. May 6 2021;28(5):816-832. doi:10.1016/j.stem.2021.04.005
25. Cordella F, Brighi C, Soloperto A, Di Angelantonio S. Stem cell-based 3D brain organoids for mimicking, investigating, and challenging Alzheimer's diseases. Neural Regen Res. Feb 2022;17(2):330-332. doi:10.4103/1673-5374.317976
26. Caffrey TM, Button EB, Robert J. Toward three-dimensional in vitro models to study neurovascular unit functions in health and disease. Neural Regen Res. Nov 2021;16(11):2132-2140. doi:10.4103/1673-5374.310671
27. Scott G, Huang Y. Engineering cerebral folding in brain organoids. Neural Regen Res. Nov 2022;17(11):2420-2422. doi:10.4103/1673-5374.335789
28. 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. Nov 6 2008;3(5):519-32. doi:10.1016/j.stem.2008.09.002
29. Qian X, Nguyen HN, Song MM, et al. Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell. May 19 2016;165(5):1238-1254. doi:10.1016/j.cell.2016.04.032
30. Giandomenico SL, Mierau SB, Gibbons GM, et al. Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output. Nat Neurosci. Apr 2019;22(4):669-679. doi:10.1038/s41593-019-0350-2
31. Qian X, Su Y, Adam CD, et al. Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation. Cell Stem Cell. May 7 2020;26(5):766-781.e9. doi:10.1016/j.stem.2020.02.002
32. Marton RM, Pașca SP. Organoid and Assembloid Technologies for Investigating Cellular Crosstalk in Human Brain Development and Disease. Trends Cell Biol. Feb 2020;30(2):133-143. doi:10.1016/j.tcb.2019.11.004
33. Marton RM, Miura Y, Sloan SA, et al. Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat Neurosci. Mar 2019;22(3):484-491. doi:10.1038/s41593-018-0316-9
34. Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. Jul 10 2020;369(6500)doi:10.1126/science.aaz5626
35. Adlakha YK. Human 3D brain organoids: steering the demolecularization of brain and neurological diseases. Cell Death Discovery. 2023/07/03 2023;9(1):221. doi:10.1038/s41420-023-01523-w
36. Yadav A, Seth B, Chaturvedi RK. Brain Organoids: Tiny Mirrors of Human Neurodevelopment and Neurological Disorders. The Neuroscientist. 2021/08/01 2020;27(4):388-426. doi:10.1177/1073858420943192
37. Rosebrock D, Arora S, Mutukula N, 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. Jun 2022;24(6):981-995. doi:10.1038/s41556-022-00929-5
38. Chen H, Jin X, Li T, Ye Z. Brain organoids: Establishment and application. Front Cell Dev Biol. 2022;10:1029873. doi:10.3389/fcell.2022.1029873
39. Makrygianni EA, Chrousos GP. From Brain Organoids to Networking Assembloids: Implications for Neuroendocrinology and Stress Medicine. Front Physiol. 2021;12:621970. doi:10.3389/fphys.2021.621970
40. Bagley JA, Reumann D, Bian S, Lévi-Strauss J, Knoblich JA. Fused cerebral organoids model interactions between brain regions. Nat Methods. Jul 2017;14(7):743-751. doi:10.1038/nmeth.4304
41. Andersen J, Revah O, Miura Y, et al. Generation of Functional Human 3D Cortico-Motor Assembloids. Cell. Dec 23 2020;183(7):1913-1929.e26. doi:10.1016/j.cell.2020.11.017
42. Samarasinghe RA, Miranda OA, Buth JE, et al. Identification of neural oscillations and epileptiform changes in human brain organoids. Nat Neurosci. Oct 2021;24(10):1488-1500. doi:10.1038/s41593-021-00906-5
43. Li Z, Li Q, Zhou C, et al. Organoid-on-a-chip: Current challenges, trends, and future scope toward medicine. Biomicrofluidics. Sep 2023;17(5):051505. doi:10.1063/5.0171350
44. Karzbrun E, Tshuva RY, Reiner O. An On-Chip Method for Long-Term Growth and Real-Time Imaging of Brain Organoids. Curr Protoc Cell Biol. Dec 2018;81(1):e62. doi:10.1002/cpcb.62
45. Mittal R, Woo FW, Castro CS, et al. Organ-on-chip models: Implications in drug discovery and clinical applications. J Cell Physiol. Jun 2019;234(6):8352-8380. doi:10.1002/jcp.27729
46. Bang S, Lee S, Choi N, Kim HN. Emerging Brain-Pathophysiology-Mimetic Platforms for Studying Neurodegenerative Diseases: Brain Organoids and Brains-on-a-Chip. Adv Healthc Mater. Jun 2021;10(12):e2002119. doi:10.1002/adhm.202002119
47. Seo Y, Bang S, Son J, et al. Brain physiome: A concept bridging in vitro 3D brain models and in silico models for predicting drug toxicity in the brain. Bioact Mater. Jul 2022;13:135-148. doi:10.1016/j.bioactmat.2021.11.009
48. Chen X, Sun G, Tian E, et al. Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure. Adv Sci (Weinh). Sep 2021;8(18):e2101462. doi:10.1002/advs.202101462
49. Szebényi K, Wenger LMD, Sun Y, et al. Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology. Nat Neurosci. Nov 2021;24(11):1542-1554. doi:10.1038/s41593-021-00923-4
50. 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. Aug 4 2016;19(2):248-257. doi:10.1016/j.stem.2016.07.005
51. Kim H, Park HJ, Choi H, et al. Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids. Stem Cell Reports. Mar 5 2019;12(3):518-531. doi:10.1016/j.stemcr.2019.01.020
52. Smits LM, Reinhardt L, Reinhardt P, et al. Modeling Parkinson’s disease in midbrain-like organoids. npj Parkinson's Disease. 2019/04/05 2019;5(1):5. doi:10.1038/s41531-019-0078-4
53. Trujillo CA, Muotri AR. Brain Organoids and the Study of Neurodevelopment. Trends Mol Med. Dec 2018;24(12):982-990. doi:10.1016/j.molmed.2018.09.005
54. Villanueva R. Advances in the knowledge and therapeutics of schizophrenia, major depression disorder, and bipolar disorder from human brain organoid research. Front Psychiatry. 2023;14:1178494. doi:10.3389/fpsyt.2023.1178494
55. Kim IB, Park SC. The Entorhinal Cortex and Adult Neurogenesis in Major Depression. Int J Mol Sci. Oct 29. 2021;22(21)doi:10.3390/ijms222111725
56. Micheli L, Ceccarelli M, D'Andrea G, Tirone F. Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise. Brain Res Bull. Oct 2018;143:181-193. doi:10.1016/j.brainresbull.2018.09.002
57. Wang Q, Dong X, Hu T, et al. Constitutive Activity of Serotonin Receptor 6 Regulates Human Cerebral Organoids Formation and Depression-like Behaviors. Stem Cell Reports. Jan 12 2021;16(1):75-88. doi:10.1016/j.stemcr.2020.11.015
58. Gunaydin LA, Kreitzer AC. Cortico-Basal Ganglia Circuit Function in Psychiatric Disease. Annu Rev Physiol. 2016;78:327-50. doi:10.1146/annurev-physiol-021115-105355
59. Theyel B. Animal Models in Psychiatric Disease: A Circuit-Search Approach. Harv Rev Psychiatry. Sep/Oct 2018;26(5):298-303. doi:10.1097/hrp.0000000000000193
60. McTeague LM, Rosenberg BM, Lopez JW, et al. Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders. Am J Psychiatry. May 1 2020;177(5):411-421. doi:10.1176/appi.ajp.2019.18111271
61. Hesdorffer DC. Comorbidity between neurological illness and psychiatric disorders. CNS Spectrums. 2016;21(3):230-238. doi:10.1017/S1092852915000929
62. Tang XY, Wu S, Wang D, et al. Human organoids in basic research and clinical applications. Signal Transduct Target Ther. May 24 2022;7(1):168. doi:10.1038/s41392-022-01024-9
63. Hinman VF, Burke RD. Embryonic neurogenesis in echinoderms. Wiley Interdiscip Rev Dev Biol. Jul 2018;7(4):e316. doi:10.1002/wdev.316
64. Gupta J, Gaurkar SS. Migraine: An Underestimated Neurological Condition Affecting Billions. Cureus. Aug 2022;14(8):e28347. doi:10.7759/cureus.28347
65. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. Apr 2017;97(2):553-622. doi:10.1152/physrev.00034.2015
66. Andreou AP, Edvinsson L. Mechanisms of migraine as a chronic evolutive condition. J Headache Pain. Dec 23 2019;20(1):117. doi:10.1186/s10194-019-1066-0
67. Cai M, Liu J, Wang X, et al. Spontaneous brain activity abnormalities in migraine: A meta-analysis of functional neuroimaging. Hum Brain Mapp. Feb 1 2023;44(2):571-584. doi:10.1002/hbm.26085
68. Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia. 2019/03/01 2017;39(3):366-373. doi:10.1177/0333102417736900
69. 69. Tardiolo G, Bramanti P, Mazzon E. Migraine: Experimental Models and Novel Therapeutic Approaches. International Journal of Molecular Sciences. 2019;20(12). doi:10.3390/ijms20122932
70. 70. Tu Y, Fu Z, Zeng F, et al. Abnormal thalamocortical network dynamics in migraine. Neurology. Jun 4 2019;92(23):e2706-e2716. doi:10.1212/wnl.0000000000007607
71. Groveman BR, Ferreira NC, Foliaki ST, et al. Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt–Jakob disease. Scientific Reports. 2021/03/09 2021;11(1):5165. doi:10.1038/s41598-021-84689-6
72. Acharya P, Choi NY, Shrestha S, Jeong S, Lee M-Y. Brain organoids: A revolutionary tool for modeling neurological disorders and development of therapeutics. Biotechnology and Bioengineering. 2023/11/28 2023;n/a(n/a) doi:https://doi.org/10.1002/bit.28606
73. Sharma A, Fernandes DC, Reis RL, et al. Cutting-edge advances in modeling the blood–brain barrier and tools for its reversible permeabilization for enhanced drug delivery into the brain. Cell & Bioscience. 2023/07/27 2023;13(1):137. doi:10.1186/s13578-023-01079-3
74. Fan P, Wang Y, Xu M, Han X, Liu Y. The Application of Brain Organoids in Assessing Neural Toxicity. Front Mol Neurosci. 2022;15:799397. doi:10.3389/fnmol.2022.799397
75. Revah O, Gore F, Kelley KW, et al. Maturation and circuit integration of transplanted human cortical organoids. Nature. 2022/10/01 2022;610(7931):319-326. doi:10.1038/s41586-022-05277-w
76. Pichl A, Ranisch R, Altinok OA, et al. Ethical, legal and social aspects of human cerebral organoids and their governance in Germany, the United Kingdom and the United States. Front Cell Dev Biol. 2023;11:1194706. doi:10.3389/fcell.2023.1194706
77. Hoppe M, Habib A, Desai R, et al. Human brain organoid code of conduct. Perspective. Frontiers in Molecular Medicine. 2023-March-23 2023;3doi:10.3389/fmmed.2023.1143298
2. Ma C, Seong H, Li X, Yu X, Xu S, Li Y. Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening. Stem Cells Int. 2022;2022:2150680. doi:10.1155/2022/2150680
3. Zhou JQ, Zeng LH, Li CT, et al. Brain organoids are new tool for drug screening of neurological diseases. Neural Regen Res. Sep 2023;18(9):1884-1889. doi:10.4103/1673-5374.367983
4. Xu J, Wen Z. Brain Organoids: Studying Human Brain Development and Diseases in a Dish. Stem Cells Int. 2021;2021:5902824. doi:10.1155/2021/5902824
5. Li Y, Zeng P-M, Wu J, Luo Z-G. Advances and Applications of Brain Organoids. Neuroscience Bulletin. 2023/11/01 2023;39(11):1703-1716. doi:10.1007/s12264-023-01065-2
6. Wang H. Modeling Neurological Diseases With Human Brain Organoids. Front Synaptic Neurosci. 2018;10:15. doi:10.3389/fnsyn.2018.00015
7. Feigin VL, Vos T, Nichols E, et al. The global burden of neurological disorders: translating evidence into policy. Lancet Neurol. Mar 2020;19(3):255-265. doi:10.1016/s1474-4422(19)30411-9
8. 8. Owolabi MO, Leonardi M, Bassetti C, et al. Global synergistic actions to improve brain health for human development. Nature Reviews Neurology. 2023/06/01 2023;19(6):371-383. doi:10.1038/s41582-023-00808-z
9. Wareham LK, Liddelow SA, Temple S, et al. Solving neurodegeneration: common mechanisms and strategies for new treatments. Molecular Neurodegeneration. 2022/03/21 2022;17(1):23. doi:10.1186/s13024-022-00524-0
10. Ningrum DNA, Kung WM. Challenges and Perspectives of Neurological Disorders. Brain Sci. Apr 18 2023;13(4)doi:10.3390/brainsci13040676
11. Markou A, Chiamulera C, Geyer MA, Tricklebank M, Steckler T. Removing Obstacles in Neuroscience Drug Discovery: The Future Path for Animal Models. Neuropsychopharmacology. 2009/01/01 2009;34(1):74-89. doi:10.1038/npp.2008.173
12. Dawson TM, Golde TE, Lagier-Tourenne C. Animal models of neurodegenerative diseases. Nat Neurosci. Oct 2018;21(10):1370-1379. doi:10.1038/s41593-018-0236-8
13. Qian L, Tcw J. Human iPSC-Based Modeling of Central Nerve System Disorders for Drug Discovery. International Journal of Molecular Sciences. 2021;22(3). doi:10.3390/ijms22031203
14. Gazerani P. Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development. Int J Mol Sci. Feb 4 2023;24(4)doi:10.3390/ijms24043113
15. Chhibber T, Bagchi S, Lahooti B, et al. CNS organoids: an innovative tool for neurological disease modeling and drug neurotoxicity screening. Drug Discov Today. Feb 2020;25(2):456-465. doi:10.1016/j.drudis.2019.11.010
16. Cherskov A, Sestan N. A screen of brain organoids to study neurodevelopmental disease. Nature. Jan 2021;589(7840):24-25. doi:10.1038/d41586-020-03636-z
17. Lancaster MA, Renner M, Martin C-A, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013/09/01 2013;501(7467):373-379. doi:10.1038/nature12517
18. Clevers H. Modeling Development and Disease with Organoids. Cell. Jun 16 2016;165(7):1586-1597. doi:10.1016/j.cell.2016.05.082
19. Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. Oct 2017;18(10):573-584. doi:10.1038/nrn.2017.107
20. Qian X, Song H, Ming GL. Brain organoids: advances, applications and challenges. Development. Apr 16 2019;146(8)doi:10.1242/dev.166074
21. Sun N, Meng X, Liu Y, Song D, Jiang C, Cai J. Applications of brain organoids in neurodevelopment and neurological diseases. Journal of Biomedical Science. 2021/04/22 2021;28(1):30. doi:10.1186/s12929-021-00728-4
22. Castiglione H, Vigneron PA, Baquerre C, Yates F, Rontard J, Honegger T. Human Brain Organoids-on-Chip: Advances, Challenges, and Perspectives for Preclinical Applications. Pharmaceutics. Oct 26 2022;14(11)doi:10.3390/pharmaceutics14112301
23. Smirnova L, Morales Pantoja IE, Hartung T. Organoid intelligence (OI) - The ultimate functionality of a brain microphysiological system. Altex. 2023;40(2):191-203. doi:10.14573/altex.2303261
24. Marsee A, Roos FJM, Verstegen MMA, et al. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids. Cell Stem Cell. May 6 2021;28(5):816-832. doi:10.1016/j.stem.2021.04.005
25. Cordella F, Brighi C, Soloperto A, Di Angelantonio S. Stem cell-based 3D brain organoids for mimicking, investigating, and challenging Alzheimer's diseases. Neural Regen Res. Feb 2022;17(2):330-332. doi:10.4103/1673-5374.317976
26. Caffrey TM, Button EB, Robert J. Toward three-dimensional in vitro models to study neurovascular unit functions in health and disease. Neural Regen Res. Nov 2021;16(11):2132-2140. doi:10.4103/1673-5374.310671
27. Scott G, Huang Y. Engineering cerebral folding in brain organoids. Neural Regen Res. Nov 2022;17(11):2420-2422. doi:10.4103/1673-5374.335789
28. 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. Nov 6 2008;3(5):519-32. doi:10.1016/j.stem.2008.09.002
29. Qian X, Nguyen HN, Song MM, et al. Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell. May 19 2016;165(5):1238-1254. doi:10.1016/j.cell.2016.04.032
30. Giandomenico SL, Mierau SB, Gibbons GM, et al. Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output. Nat Neurosci. Apr 2019;22(4):669-679. doi:10.1038/s41593-019-0350-2
31. Qian X, Su Y, Adam CD, et al. Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation. Cell Stem Cell. May 7 2020;26(5):766-781.e9. doi:10.1016/j.stem.2020.02.002
32. Marton RM, Pașca SP. Organoid and Assembloid Technologies for Investigating Cellular Crosstalk in Human Brain Development and Disease. Trends Cell Biol. Feb 2020;30(2):133-143. doi:10.1016/j.tcb.2019.11.004
33. Marton RM, Miura Y, Sloan SA, et al. Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat Neurosci. Mar 2019;22(3):484-491. doi:10.1038/s41593-018-0316-9
34. Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. Jul 10 2020;369(6500)doi:10.1126/science.aaz5626
35. Adlakha YK. Human 3D brain organoids: steering the demolecularization of brain and neurological diseases. Cell Death Discovery. 2023/07/03 2023;9(1):221. doi:10.1038/s41420-023-01523-w
36. Yadav A, Seth B, Chaturvedi RK. Brain Organoids: Tiny Mirrors of Human Neurodevelopment and Neurological Disorders. The Neuroscientist. 2021/08/01 2020;27(4):388-426. doi:10.1177/1073858420943192
37. Rosebrock D, Arora S, Mutukula N, 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. Jun 2022;24(6):981-995. doi:10.1038/s41556-022-00929-5
38. Chen H, Jin X, Li T, Ye Z. Brain organoids: Establishment and application. Front Cell Dev Biol. 2022;10:1029873. doi:10.3389/fcell.2022.1029873
39. Makrygianni EA, Chrousos GP. From Brain Organoids to Networking Assembloids: Implications for Neuroendocrinology and Stress Medicine. Front Physiol. 2021;12:621970. doi:10.3389/fphys.2021.621970
40. Bagley JA, Reumann D, Bian S, Lévi-Strauss J, Knoblich JA. Fused cerebral organoids model interactions between brain regions. Nat Methods. Jul 2017;14(7):743-751. doi:10.1038/nmeth.4304
41. Andersen J, Revah O, Miura Y, et al. Generation of Functional Human 3D Cortico-Motor Assembloids. Cell. Dec 23 2020;183(7):1913-1929.e26. doi:10.1016/j.cell.2020.11.017
42. Samarasinghe RA, Miranda OA, Buth JE, et al. Identification of neural oscillations and epileptiform changes in human brain organoids. Nat Neurosci. Oct 2021;24(10):1488-1500. doi:10.1038/s41593-021-00906-5
43. Li Z, Li Q, Zhou C, et al. Organoid-on-a-chip: Current challenges, trends, and future scope toward medicine. Biomicrofluidics. Sep 2023;17(5):051505. doi:10.1063/5.0171350
44. Karzbrun E, Tshuva RY, Reiner O. An On-Chip Method for Long-Term Growth and Real-Time Imaging of Brain Organoids. Curr Protoc Cell Biol. Dec 2018;81(1):e62. doi:10.1002/cpcb.62
45. Mittal R, Woo FW, Castro CS, et al. Organ-on-chip models: Implications in drug discovery and clinical applications. J Cell Physiol. Jun 2019;234(6):8352-8380. doi:10.1002/jcp.27729
46. Bang S, Lee S, Choi N, Kim HN. Emerging Brain-Pathophysiology-Mimetic Platforms for Studying Neurodegenerative Diseases: Brain Organoids and Brains-on-a-Chip. Adv Healthc Mater. Jun 2021;10(12):e2002119. doi:10.1002/adhm.202002119
47. Seo Y, Bang S, Son J, et al. Brain physiome: A concept bridging in vitro 3D brain models and in silico models for predicting drug toxicity in the brain. Bioact Mater. Jul 2022;13:135-148. doi:10.1016/j.bioactmat.2021.11.009
48. Chen X, Sun G, Tian E, et al. Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure. Adv Sci (Weinh). Sep 2021;8(18):e2101462. doi:10.1002/advs.202101462
49. Szebényi K, Wenger LMD, Sun Y, et al. Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology. Nat Neurosci. Nov 2021;24(11):1542-1554. doi:10.1038/s41593-021-00923-4
50. 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. Aug 4 2016;19(2):248-257. doi:10.1016/j.stem.2016.07.005
51. Kim H, Park HJ, Choi H, et al. Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids. Stem Cell Reports. Mar 5 2019;12(3):518-531. doi:10.1016/j.stemcr.2019.01.020
52. Smits LM, Reinhardt L, Reinhardt P, et al. Modeling Parkinson’s disease in midbrain-like organoids. npj Parkinson's Disease. 2019/04/05 2019;5(1):5. doi:10.1038/s41531-019-0078-4
53. Trujillo CA, Muotri AR. Brain Organoids and the Study of Neurodevelopment. Trends Mol Med. Dec 2018;24(12):982-990. doi:10.1016/j.molmed.2018.09.005
54. Villanueva R. Advances in the knowledge and therapeutics of schizophrenia, major depression disorder, and bipolar disorder from human brain organoid research. Front Psychiatry. 2023;14:1178494. doi:10.3389/fpsyt.2023.1178494
55. Kim IB, Park SC. The Entorhinal Cortex and Adult Neurogenesis in Major Depression. Int J Mol Sci. Oct 29. 2021;22(21)doi:10.3390/ijms222111725
56. Micheli L, Ceccarelli M, D'Andrea G, Tirone F. Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise. Brain Res Bull. Oct 2018;143:181-193. doi:10.1016/j.brainresbull.2018.09.002
57. Wang Q, Dong X, Hu T, et al. Constitutive Activity of Serotonin Receptor 6 Regulates Human Cerebral Organoids Formation and Depression-like Behaviors. Stem Cell Reports. Jan 12 2021;16(1):75-88. doi:10.1016/j.stemcr.2020.11.015
58. Gunaydin LA, Kreitzer AC. Cortico-Basal Ganglia Circuit Function in Psychiatric Disease. Annu Rev Physiol. 2016;78:327-50. doi:10.1146/annurev-physiol-021115-105355
59. Theyel B. Animal Models in Psychiatric Disease: A Circuit-Search Approach. Harv Rev Psychiatry. Sep/Oct 2018;26(5):298-303. doi:10.1097/hrp.0000000000000193
60. McTeague LM, Rosenberg BM, Lopez JW, et al. Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders. Am J Psychiatry. May 1 2020;177(5):411-421. doi:10.1176/appi.ajp.2019.18111271
61. Hesdorffer DC. Comorbidity between neurological illness and psychiatric disorders. CNS Spectrums. 2016;21(3):230-238. doi:10.1017/S1092852915000929
62. Tang XY, Wu S, Wang D, et al. Human organoids in basic research and clinical applications. Signal Transduct Target Ther. May 24 2022;7(1):168. doi:10.1038/s41392-022-01024-9
63. Hinman VF, Burke RD. Embryonic neurogenesis in echinoderms. Wiley Interdiscip Rev Dev Biol. Jul 2018;7(4):e316. doi:10.1002/wdev.316
64. Gupta J, Gaurkar SS. Migraine: An Underestimated Neurological Condition Affecting Billions. Cureus. Aug 2022;14(8):e28347. doi:10.7759/cureus.28347
65. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. Apr 2017;97(2):553-622. doi:10.1152/physrev.00034.2015
66. Andreou AP, Edvinsson L. Mechanisms of migraine as a chronic evolutive condition. J Headache Pain. Dec 23 2019;20(1):117. doi:10.1186/s10194-019-1066-0
67. Cai M, Liu J, Wang X, et al. Spontaneous brain activity abnormalities in migraine: A meta-analysis of functional neuroimaging. Hum Brain Mapp. Feb 1 2023;44(2):571-584. doi:10.1002/hbm.26085
68. Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia. 2019/03/01 2017;39(3):366-373. doi:10.1177/0333102417736900
69. 69. Tardiolo G, Bramanti P, Mazzon E. Migraine: Experimental Models and Novel Therapeutic Approaches. International Journal of Molecular Sciences. 2019;20(12). doi:10.3390/ijms20122932
70. 70. Tu Y, Fu Z, Zeng F, et al. Abnormal thalamocortical network dynamics in migraine. Neurology. Jun 4 2019;92(23):e2706-e2716. doi:10.1212/wnl.0000000000007607
71. Groveman BR, Ferreira NC, Foliaki ST, et al. Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt–Jakob disease. Scientific Reports. 2021/03/09 2021;11(1):5165. doi:10.1038/s41598-021-84689-6
72. Acharya P, Choi NY, Shrestha S, Jeong S, Lee M-Y. Brain organoids: A revolutionary tool for modeling neurological disorders and development of therapeutics. Biotechnology and Bioengineering. 2023/11/28 2023;n/a(n/a) doi:https://doi.org/10.1002/bit.28606
73. Sharma A, Fernandes DC, Reis RL, et al. Cutting-edge advances in modeling the blood–brain barrier and tools for its reversible permeabilization for enhanced drug delivery into the brain. Cell & Bioscience. 2023/07/27 2023;13(1):137. doi:10.1186/s13578-023-01079-3
74. Fan P, Wang Y, Xu M, Han X, Liu Y. The Application of Brain Organoids in Assessing Neural Toxicity. Front Mol Neurosci. 2022;15:799397. doi:10.3389/fnmol.2022.799397
75. Revah O, Gore F, Kelley KW, et al. Maturation and circuit integration of transplanted human cortical organoids. Nature. 2022/10/01 2022;610(7931):319-326. doi:10.1038/s41586-022-05277-w
76. Pichl A, Ranisch R, Altinok OA, et al. Ethical, legal and social aspects of human cerebral organoids and their governance in Germany, the United Kingdom and the United States. Front Cell Dev Biol. 2023;11:1194706. doi:10.3389/fcell.2023.1194706
77. Hoppe M, Habib A, Desai R, et al. Human brain organoid code of conduct. Perspective. Frontiers in Molecular Medicine. 2023-March-23 2023;3doi:10.3389/fmmed.2023.1143298