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Human organoids to model the developing human neocortex in health and disease.
Rodent models have catalyzed major discoveries in the neocortex, a brain region unique to mammals. However, since the neocortex has expanded considerably in primates, employing rodent models has limitations. Human fetal brain tissue is a scarce resource with limitations for experimental manipulations. In order to create an experimentally tractable representation of human brain development, a number of labs have recently created in vitro models of the developing human brain. These models, generated using human embryonic stem cells or induced pluripotent stem cells, are called "organoids". Organoids have successfully and rapidly uncovered new mechanisms of human brain development in health and disease. In the future, we envision that this strategy will enable faster and more efficient translation of basic neuroscience findings to therapeutic applications. In this review, we discuss the generation of the first human cerebral organoids, progress since their debut, and challenges to be overcome in the future.
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Microcephaly-like phenotype triggered by novel reassortant and prototypic Oropouche virus strains in brain organoids.
BACKGROUND: Oropouche virus (OROV) is an emerging arbovirus currently spreading across South America, with increasing reports of neurological manifestations, severe systemic disease, and congenital abnormalities. Although traditionally associated with mild febrile illness, the recent geographic expansion and surge in OROV outbreaks have prompted attention to its neurotropic potential. METHODS: We investigated the effects of Oropouche virus (OROV) infection on neural stem cells (NSCs) and brain organoids derived from human induced pluripotent stem cells, using both an emergent reassortant isolate and a prototypical strain. FINDINGS: OROV infected NSCs, leading to cell death, depletion of proliferative progenitors, and disruption of neuroepithelial organisation. Transcriptomic profiling revealed reduction of antiviral response genes and enrichment of signalling pathways related to viral replication, apoptosis, and inhibition of stem cell maintenance and neuronal differentiation. These molecular signatures aligned with phenotypic collapse of progenitor pools and cortical structure observed in organoids, in which OROV infected progenitors, neurons and astrocytes. Proteomic analysis of brain organoids infected with OROV showed regulation of neurodevelopment pathways, which have been previously associated with ZIKV infection, suggesting convergent pathway disruption associated with reduced growth of organoids infected by ZIKV and OROV and highlighting their potential to impair brain development. INTERPRETATION: These results reveal evidence consistent with a previously unrecognised neurodevelopmental pathogenic potential of OROV strains and provide mechanistic insight into their contribution to microcephaly-like outcomes. FUNDING: D'Or Institute, ITpS, CNPq, FAPEMIG, FAPERJ.
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The presence of BBB hastens neuronal differentiation of cerebral organoids - The potential role of endothelial derived BDNF.
Despite remaining the best in vitro model to resemble the human brain, a weakness of human cerebral organoids is the lack of the endothelial component that in vivo organizes in the blood brain barrier (BBB). Since the BBB is crucial to control the microenvironment of the nervous system, this study proposes a co-culture of BBB and cerebral organoids. We utilized a BBB model consisting of primary human brain microvascular endothelial cells and astrocytes in a transwell system. Starting from induced Pluripotent Stem Cells (iPSCs) we generated human cerebral organoids which were then cultured in the absence or presence of an in vitro model of BBB to evaluate potential effects on the maturation of cerebral organoids. By morphological analysis, it emerges that in the presence of the BBB the cerebral organoids are better organized than controls in the absence of the BBB. This effect might be due to Brain Derived Neurotrophic Factor (BDNF), a neurotrophic factor released by the endothelial component of the BBB, which is involved in neurodevelopment, neuroplasticity and neurosurvival.
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Human brain 'organoids' grafted into rats take note of light and pattern.
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Advances in Human Brain Organoids: Methodological Innovations and Future Directions for Drug Discovery.
BACKGROUND: Understanding the genetic foundations of brain development has been made possible by the use of traditional biological models. However, these models frequently fail to capture the complexity of human brain development, particularly the considerable cortical expansion that sets humans apart from other vertebrates and non-human primates. OBJECTIVES: The purpose of this review is to outline the methodology, applications, and potential prospects for using human brain organoids as sophisticated models for researching brain development and illness mechanisms. METHODS: Organoids, or three-dimensional (3-D) structures, are generated by utilizing adult or embryonic stem cells to mimic the main structural and functional features of the human brain. The present investigation emphasizes the advantages of these organoids over traditional two-dimensional (2-D) monolayer models in relation to cellular variety and the ability to create complex 3-D networks, addressing various methods established by researchers to culture these cells. RESULTS: Organoids precisely mimic numerous features of human brain development, overcoming the limitations of conventional models. They have demonstrated significant utility in investigating the mechanisms that contribute to neurodegenerative diseases like Parkinson's and Alzheimer's, in addition to tumor biology, providing a valuable understanding of both the normal physiological processes and the underlying cause of the human brain. CONCLUSION: Human brain organoids signify a notable progression in the field of neuroscience research, facilitating enhanced modeling of brain disorders. Future investigations will further enhance these methodologies and examine their applications, leading to innovative therapeutic strategies and broadening the knowledge of human brain disorders.
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Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways.
Identifying genes whose expression is associated with schizophrenia (SCZ) risk by transcriptome-wide association studies (TWAS) facilitates downstream experimental studies. Here, we integrated multiple published datasets of TWAS, gene coexpression, and differential gene expression analysis to prioritize SCZ candidate genes for functional study. Convergent evidence prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB), a nuclear-encoded mitochondrial gene, as an SCZ risk gene. However, the PCCB's contribution to SCZ risk has not been investigated before. Using dual luciferase reporter assay, we identified that SCZ-associated SNPs rs6791142 and rs35874192, two eQTL SNPs for PCCB, showed differential allelic effects on transcriptional activities. PCCB knockdown in human forebrain organoids (hFOs) followed by RNA sequencing analysis revealed dysregulation of genes enriched with multiple neuronal functions including gamma-aminobutyric acid (GABA)-ergic synapse. The metabolomic and mitochondrial function analyses confirmed the decreased GABA levels resulted from inhibited tricarboxylic acid cycle in PCCB knockdown hFOs. Multielectrode array recording analysis showed that PCCB knockdown in hFOs resulted into SCZ-related phenotypes including hyper-neuroactivities and decreased synchronization of neural network. In summary, this study utilized hFOs-based multi-omics analyses and revealed that PCCB downregulation may contribute to SCZ risk through regulating GABAergic pathways, highlighting the mitochondrial function in SCZ.
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Chimeric brain organoids capture human genetic diversity.
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Brain and Retinal Organoids for Disease Modeling: The Importance of In Vitro Blood-Brain and Retinal Barriers Studies.
Brain and retinal organoids are functional and dynamic in vitro three-dimensional (3D) structures derived from pluripotent stem cells that spontaneously organize themselves to their in vivo counterparts. Here, we review the main literature data of how these organoids have been developed through different protocols and how they have been technically analyzed. Moreover, this paper reviews recent advances in using organoids to model neurological and retinal diseases, considering their potential for translational applications but also pointing out their limitations. Since the blood-brain barrier (BBB) and blood-retinal barrier (BRB) are understood to play a fundamental role respectively in brain and eye functions, both in health and in disease, we provide an overview of the progress in the development techniques of in vitro models as reliable and predictive screening tools for BBB and BRB-penetrating compounds. Furthermore, we propose potential future directions for brain and retinal organoids, in which dedicated biobanks will represent a novel tool for neuroscience and ophthalmology research.
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Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines.
The repertoire of neurons and their progenitors depends on their location along the antero-posterior and dorso-ventral axes of the neural tube. To model these axes, we designed the Dual Orthogonal-Morphogen Assisted Patterning System (Duo-MAPS) diffusion device to expose spheres of induced pluripotent stem cells (iPSCs) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison with single-cell transcriptomes from the fetal human brain revealed that Duo-MAPS-patterned organoids generated an extensive diversity of neuronal lineages from the forebrain, midbrain, and hindbrain. WNT and SHH crosstalk translated into early patterns of gene expression programs associated with the generation of specific brain lineages with distinct functional networks. Human iPSC lines showed substantial interindividual and line-to-line variations in their response to morphogens, highlighting that genetic and epigenetic variations may influence regional specification. Morphogen gradients promise to be a key approach to model the brain in its entirety.
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Cellular interplay in brain organoids: Connecting cell-autonomous and non-cell-autonomous mechanisms in neurodevelopmental disease.
The field of brain organoids has experienced a period of rapid and transformative growth, enabling researchers to investigate complex human biological mechanisms that were previously deemed intractable. This review provides an overview of the current landscape of brain organoids, with a particular focus on their relevance in the context of neurodevelopmental disorders. It also emphasizes the crucial role these models play in elucidating both cell-autonomous and non-cell-autonomous mechanisms. We describe how these two mechanisms, often considered to be independent, are intricately interconnected. In conclusion, this review aims to highlight how the utilization of brain organoids has considerably advanced our comprehension of neurodevelopmental disorders, while also delineating prospective avenues for investigating these complex conditions.