Abstract
Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.
Highlights
Given the limited accessibility to human brain tissue, most of the knowledge about brain development comes from studies in animals
In brain organoids of the medial ganglionic eminence, the expression of GABA synthesis enzymes and vesicular GABA transporter genes were highly enriched after 1 month, while GABAergic synapses were confirmed by immunohistochemistry after 2 months in culture (Xiang et al, 2017)
Rodents have been heavily used in multiple studies, but limitations to replicate brain cytoarchitecture complexity; formation of protein aggregates characteristic of neurodegenerative pathologies, and differential susceptibility to pathogens have hindered to address important aspects of developmental and neurodegenerative disorders; and pathogen invasion into the brain [reviewed in Gerakis and Hetz (2019), Marshall and Mason (2019)]. iPSC from patients containing mutations in causal genes and iPSC with mutations introduced by CRISPR/Cas9 have been used to produce brain organoid models for multiple diseases (Sidhaye and Knoblich, 2021)
Summary
Given the limited accessibility to human brain tissue, most of the knowledge about brain development comes from studies in animals. Brain organoids have been referred to as cellular aggregates resembling brain regions under development. They allowed for a better comprehension of cell division processes in the human brain. The Age of Brain Organoids of this live model of the human brain are mostly symmetrical This is in contrast to the observed in the mouse brain, which presents mixed symmetrical/asymmetrical divisions. Human brain organoids can be generated by non-guided protocols in which the neural tissue develops from intrinsic cues. This results in brain organoids displaying domains that resemble multiple brain regions (Lancaster et al, 2013; Quadrato et al, 2017). The idea is to paint a picture of organoid functionality based on maturity and how that can be applied in the context of disease modeling
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