Challenges and future perspectives for 3D cerebral organoids as a model for complex brain disorders

Keywords: cerebral organoids, 3D culture, microfluidic platform, precision medicine

Abstract

The human brain is made up of billions of neurons and glial cells which are interconnected and organized into specific patterns of neural circuitry, and hence is arguably the most sophisticated organ in human, both structurally and functionally. Studying the underlying mechanisms responsible for neurological or neurodegenerative disorders and the developmental basis of complex brain diseases such as autism, schizophrenia, bipolar disorder, Alzheimer’s and Parkinson’s disease has proven challenging due to practical and ethical limitations on experiments with human material and the limitations of existing biological/animal models. Recently, cerebral organoids have been proposed as a promising and revolutionary model for understanding complex brain disorders and preclinical drug screening.

References

Bergmann S, Lawler SE, Qu Y, Fadzen CM, Wolfe JM, Regan MS, et al. Blood-brain-barrier organoids for investigating the permeability of CNS therapeutics. Nat Protoc. 2018;13(12):2827-2843. https://doi.org/10.1038/s41596-018-0066-x

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(8):631-639. https://doi.org/10.1038/s41592-018-0070-7

Bilimoria PM, Stevens B. Microglia function during brain development: New insights from animal models. Brain Res. 2014;1617:7-17. https://doi.org/10.1016/j.brainres.2014.11.032

Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017;18(10):573-584. https://doi.org/10.1038/nrn.2017.107

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. Cell Stem Cell. 2008;3(5):519-532. https://doi.org/10.1016/j.stem.2008.09.002

Hickman S, Izzy S, Sen P, Morsett L, Khoury El J. Microglia in neurodegeneration. Nat Neurosci. 2018;21(10):1359-1369. https://doi.org/10.1038/s41593-018-0242-x

Iakobachvili N, Peters PJ. Humans in a Dish: The Potential of Organoids in Modeling Immunity and Infectious Diseases. Front Microbiol. 2017;8:2402. https://doi.org/10.3389/fmicb.2017.02402

Karzbrun E, Kshirsagar A, Cohen SR, Hanna JH, Reiner O. Human Brain Organoids on a Chip Reveal the Physics of Folding. Nat Phys. 2018;14(5):515-522. https://doi.org/10.1038/s41567-018-0046-7

Kelava I, Lancaster MA. Dishing out mini-brains: Current progress and future prospects in brain organoid research. Dev Biol. 2016;420(2):199-209. https://doi.org/10.1016/j.ydbio.2016.06.037

Kelava I, Lancaster MA. Stem Cell Models of Human Brain Development. Cell Stem Cell. 2016;18(6):736-748. https://doi.org/10.1016/j.stem.2016.05.022

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(7467):373-379. https://doi.org/10.1038/nature12517

Lauschke K, Frederiksen L, Hall VJ. Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells. Stem Cells Dev. 2017;26(12):857-874. https://doi.org/10.1089/scd.2017.0003

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(5):432-441. https://doi.org/10.1038/nbt.4127

Neal JT, Li X, Zhu J, Giangarra V, Grzeskowiak CL, Ju J, et al. Organoid Modeling of the Tumor Immune Microenvironment. Cell. 2018;175(7):1972-1988.e16. https://doi.org/10.1016/j.cell.2018.11.021

Ogawa J, Pao GM, Shokhirev MN, Verma IM. Glioblastoma Model Using Human Cerebral Organoids. Cell Rep. 2018;23(4):1220-1229. https://doi.org/10.1016/j.celrep.2018.03.105

Ormel PR, de Sá RV, van Bodegraven EJ, Karst H, Harschnitz O, Sneeboer MAM, et al. Microglia innately develop within cerebral organoids. Nat Commun. 2018;9(1):4167. https://doi.org/10.1038/s41467-018-06684-2

Osaki T, Sivathanu V, Kamm RD. Engineered 3D vascular and neuronal networks in a microfluidic platform. Sci Rep. 2018;8(1):5168. https://doi.org/10.1038/s41598-018-23512-1

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(7652):48-53. https://doi.org/10.1038/nature22047

van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015;161(4):933-945. https://doi.org/10.1016/j.cell.2015.03.053

Watanabe K, Kamiya D, Nishiyama A, Katayama T, Nozaki S, Kawasaki H, et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci. 2005;8(3):288-296. https://doi.org/10.1038/nn1402

Yakoub AM, Sadek M. Development and Characterization of Human Cerebral Organoids: An Optimized Protocol. Cell Transplant. 2018;27(3):393-406. https://doi.org/10.1177/0963689717752946

Zhang SC, Wernig M, Duncan ID, Brüstle O, Thomson JA. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol. 2001;19(12):1129-1133. https://doi.org/10.1038/nbt1201-1129

Published
2019-01-12
How to Cite
Cheah, P.-S., Mason, J. and Ling, K. H. (2019) “Challenges and future perspectives for 3D cerebral organoids as a model for complex brain disorders”, Neuroscience Research Notes, 2(1), pp. 1-6. doi: 10.31117/neuroscirn.v2i1.28.
Section
Editorial