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Brain organoids: an ensemble of bioassays to investigate human neurodevelopment and disease

Abstract

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.

Facts

  • 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.

Open question

  • 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.

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Fig. 1: Schematic representation of general brain organoid culture scheme.
Fig. 2: Brain organoid technologies.
Fig. 3: Neurodevelopmental patterning principles and region-specific brain organoid culture protocols.

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Acknowledgements

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).

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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

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