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Using brain organoids to study human neurodevelopment, evolution and disease

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Abstract The brain is one of the most complex organs, responsible for the advanced intellectual and cognitive ability of humans. Although primates are to some extent capable of performing cognitive tasks, their abilities are less evolved. One of the reasons for this is the vast differences in the brain of humans compared to other mammals, in terms of shape, size and complexity. Such differences make the study of human brain development fascinating. Interestingly, the cerebral cortex is by far the most complex brain region resulting from its selective evolution within mammals over millions of years. Unraveling the molecular and cellular mechanisms regulating brain development, as well as the evolutionary differences seen across species and the need to understand human brain disorders, are some of the reasons why scientists are interested in improving their current knowledge on human corticogenesis. Toward this end, several animal models including primates have been used, however, these models are limited in their extent to recapitulate human‐specific features. Recent technological achievements in the field of stem cell research, which have enabled the generation of human models of corticogenesis, called brain or cerebral organoids, are of great importance. This review focuses on the main cellular and molecular features of human corticogenesis and the use of brain organoids to study it. We will discuss the key differences between cortical development in human and nonhuman mammals, the technological applications of brain organoids and the different aspects of cortical development in normal and pathological conditions, which can be modeled using brain organoids. This article is categorized under: Comparative Development and Evolution > Regulation of Organ Diversity Nervous System Development > Vertebrates: General Principles
Major technical applications for analyzing cerebral organoids. Scheme of the major techniques that can be applied in cerebral organoids to model human cortical development, evolution and disease. (a, b). Cell type specific markers can be used to perform either (a), immunohistochemistry and in situ hybridisation to study the cytoarchitecture of the cerebral organoids and to gain insight on the spatial organization of the developing human cortex or (b) FACS to isolate specific cell types. (c). Electroporation of cerebral organoids using constructs carrying fluorophores allows the specific labeling of cells in the neuroepithelium that can then be live imaged to study different cell functions, such as cell movement, division or migration. (d). Functional techniques such as electrophysiology are applicable in cerebral organoids enabling the measurement of neuronal activity of the different neurons. (e). Finally dissociation of the cerebral organoids into single cells and then application of bulk or single‐cell‐RNA sequencing allows us to decipher the transcriptional profile of the different cell types composing the cerebral organoids. Abbreviations: IP, intermediate progenitor; a/bRG, apical/basal radial glial cell; sc‐RNA‐seq, single cell RNA sequencing
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Generation of cerebral organoids with genomic alterations. (a, b) The genome of cerebral organoids can be modified either permanently (a) or acutely (b). Introduction of a permanent specific variation is performed at the level of the iPSCs. It can be achieved either by isolating somatic cells from human patients, carrying a specific genomic variation, that are then reprogrammed to iPSCs (a1), or editing the genome of control iPSCs using the CRISPR Cas9 system (a2). Acute genome alterations can be done at a desirable time point via electroporation of a plasmid or via viral infection in the organoids (b). This method allows the manipulation of a small number of cells, which upon manipulation develop in a control environment. Abbreviations: iPSCs, induced pluripotent stem cells; CO, cerebral organoid; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; sgRNA, single guided RNA
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Schematic representation of human cortical development. (a) During the early stages of human corticogenesis (GW5‐GW11) the SVZ of the developing cortex inner and outer SVZ are not separated and the bRGs population is limited. Within the neurogenic zones, NPCs divide either symmetrically or asymmetrically generating new neurons that follow the radial glial fibers to migrate towards the developing cortical plate. The cortical plate is colonized by early born neurons, of which the number is still small and thus the cortex has no obvious gyri nor sulci. (b) From GW11, the number of bRGs is increased, the SVZ is very much expanded and the iSVZ and oSVZ are founded. Both apical and basal progenitors perform many rounds of divisions, which result in the increase of the progenitor pool and consequently neurons. Thus, the number of neurons reaching the developing cortical plate is increased resulting in the generation of folds. The number of bRGs present in the radial columns below the gyri is increased comparing to the respective number in the radial columns below the sulci. Abbreviations: GW, gestational week; VZ, ventricular zone; SVZ, subventricular zone; iSVZ, inner subventricular zone; oSVZ, outer subventricular zone; IZ, intermediate zone; SP, subplate; CP, cortical plate
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Brain organoids are a human‐specific model for studying brain development, evolution and disease. (a–c) Cerebral organoids can be used as a model of human brain development (a), evolution (b) and brain related disorders (c). Key questions regarding human brain development, such as cellular lineage progression and brain morphology in a human‐specific environment, can be answered augmenting our current knowledge (a). With the use of iPSCs from different species the evolutionary changes among mammals, primates or humans can be addressed. The genomic manipulation of organoids can be used as a great tool to understand the cellular and molecular mechanisms disrupted in brain related disorders (c). This information can be then used in personalized medicine for treatment of developmental, genetic and neurodegenerative disorders
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