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Human brain development through the lens of cerebral organoid models.
The brain is one of the most complex organs in the body, which emerges from a relatively simple set of basic 'building blocks' during early development according to complex cellular and molecular events orchestrated through a set of inherited instructions. Innovations in stem cell technologies have enabled modelling of neural cells using two- and three-dimensional cultures. In particular, cerebral ('brain') organoids have taken the center stage of brain development models that have the potential for providing meaningful insight into human neurodevelopmental and neurological disorders. We review the current understanding of cellular events during human brain organogenesis, and the events occurring during cerebral organoid differentiation. We highlight the strengths and weaknesses of this experimental model system. In particular, we explain evidence that organoids can mimic many aspects of early neural development, including neural induction, patterning, and broad neurogenesis and gliogenesis programs, offering the opportunity to study genetic regulation of these processes in a human context. Several shortcomings of the current culture methods limit the utility of cerebral organoids to spontaneously give rise to many important cell types, and to model higher order features of tissue organization. We suggest that future studies aim to improve these features in order to make them better models for the study of laminar organization, circuit formation and how disruptions of these processes relate to disease.
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Brain Organoid Transplantation: A Comprehensive Guide to the Latest Advances and Practical Applications-A Systematic Review.
Brain organoid technology has seen significant development in recent years. This self-organized, three-dimensional, organ-oriented brain tissue model can recapitulate the process of neurogenesis and consists of diverse cell types and cellular architecture. Transplanting brain organoids in vivo could be a potential tool from bench to clinical research and has been studied for many purposes. To investigate and summarize the methodology, findings, and applications of this novel technique from current evidence, we conducted this systematic review by searching PubMed and the Embase databases for the literature ranging from 2013 to 2024. A total of 480 articles were identified, and 24 of them met the inclusion criteria. The results revealed that brain organoid transplantation had promising graft survival, neural proliferation, differentiation, and maturation, axonal growth, and functional integration into the host neuronal circuit, and has been applied to multiple applications, such as therapeutic usage, cell study platforms, and disease modeling. However, heterogeneity among studies, some significant challenges, and ethical issues remain to be considered. This comprehensive review will provide an update of what is known about this powerful, innovative method and discuss some practical aspects for future research.
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Cerebral Organoids as an Experimental Platform for Human Neurogenomics.
The cerebral cortex forms early in development according to a series of heritable neurodevelopmental instructions. Despite deep evolutionary conservation of the cerebral cortex and its foundational six-layered architecture, significant variations in cortical size and folding can be found across mammals, including a disproportionate expansion of the prefrontal cortex in humans. Yet our mechanistic understanding of neurodevelopmental processes is derived overwhelmingly from rodent models, which fail to capture many human-enriched features of cortical development. With the advent of pluripotent stem cells and technologies for differentiating three-dimensional cultures of neural tissue in vitro, cerebral organoids have emerged as an experimental platform that recapitulates several hallmarks of human brain development. In this review, we discuss the merits and limitations of cerebral organoids as experimental models of the developing human brain. We highlight innovations in technology development that seek to increase its fidelity to brain development in vivo and discuss recent efforts to use cerebral organoids to study regeneration and brain evolution as well as to develop neurological and neuropsychiatric disease models.
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Cerebral organoids as tools to identify the developmental roots of autism.
Some autism spectrum disorders (ASD) likely arise as a result of abnormalities during early embryonic development of the brain. Studying human embryonic brain development directly is challenging, mainly due to ethical and practical constraints. However, the recent development of cerebral organoids provides a powerful tool for studying both normal human embryonic brain development and, potentially, the origins of neurodevelopmental disorders including ASD. Substantial evidence now indicates that cerebral organoids can mimic normal embryonic brain development and neural cells found in organoids closely resemble their in vivo counterparts. However, with prolonged culture, significant differences begin to arise. We suggest that cerebral organoids, in their current form, are most suitable to model earlier neurodevelopmental events and processes such as neurogenesis and cortical lamination. Processes implicated in ASDs which occur at later stages of development, such as synaptogenesis and neural circuit formation, may also be modeled using organoids. The accuracy of such models will benefit from continuous improvements to protocols for organoid differentiation.
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Media portrayal of ethical and social issues in brain organoid research.
BACKGROUND: Human brain organoids are a valuable research tool for studying brain development, physiology, and pathology. Yet, a host of potential ethical concerns are inherent in their creation. There is a growing group of bioethicists who acknowledge the moral imperative to develop brain organoid technologies and call for caution in this research. Although a relatively new technology, brain organoids and their uses are already being discussed in media literature. Media literature informs the public and policymakers but has the potential for utopian or dystopian distortions. Thus, it is important to understand how this technology is portrayed to the public. METHODS: To investigate how brain organoids are displayed to the public, we conducted a systematic review of media literature indexed in the Nexis Uni database from 2013-2019. News and media source articles passing exclusion criteria (n = 93) were scored to evaluate tone and relevant themes. Themes were validated with a pilot sample before being applied to the dataset. Thematic analysis assessed article tone, reported potential for the technology, and the scientific, social, and ethical contexts surrounding brain organoids research. RESULTS: Brain organoid publications became more frequent from 2013 to 2019. We observed increases in positively and negatively toned articles, suggesting growing polarization. While many sources discuss realistic applications of brain organoids, others suggest treatment and cures beyond the scope of the current technology. This could work to overhype the technology and disillusion patients and families by offering false hope. In the ethical narrative we observe a preoccupation with issues such as development of artificial consciousness and "humanization" of organoid-animal chimeras. Issues of regulation, ownership, and accuracy of the organoid models are rarely discussed. CONCLUSIONS: Given the power that media have to inform or misinform the public, it is important this literature provides an accurate and balanced reflection of the therapeutic potential and associated ethical issues regarding brain organoid research. Our study suggests increasing polarization, coupled with misplaced and unfounded ethical concern. Given the inhibitory effects of public fear or disillusion on research funding, it is important media literature provides an accurate reflection of brain organoids.
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Parsing the effect of co-culture with brain organoids on Diffuse Intrinsic Pontine Glioma (DIPG) using quantitative proteomics.
Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly brain cancers in children for which there is no effective treatment. This can partly be attributed to preclinical models that lack essential elements of the in vivo tissue environment, resulting in treatments that appear promising preclinically, but fail to result in effective cures. Recently developed co-culture models combining stem cell-derived brain organoids with brain cancer cells provide tissue dimensionality and a human-relevant tissue-like microenvironment. As these models are technically challenging, we aimed to establish whether interaction with the organoid influences DIPG biology and thus warrants their use. To address this question DIPG24 cells were cultured with pluripotent stem cell-derived cortical organoids. We created "mosaic" co-cultures enriched for tumour cell-neuronal cell interactions versus "assembloid" co-cultures enriched for tumour cell-tumour cell interactions. Sequential window acquisition of all theoretical mass spectra (SWATH-MS) was used to analyse the proteomes of DIPG fractions isolated by flow-assisted cell sorting. Control proteomes from DIPG spheroids were compared with DIPG cells isolated from mosaic and assembloid co-cultures. This suggested changes in cell interaction with the external environment reflected by decreased gene ontology terms associated with adhesion and extracellular matrix, and increased DNA synthesis and replication, in DIPG24 cells under either co-culture condition. By contrast, the mosaic co-culture was associated with neuron-specific brahma-associated factor (nBAF) complex signalling, a process associated with neuronal maturation. We propose that co-culture with brain organoids is a valuable tool to parse the contribution of the brain microenvironment to DIPG tumour biology.
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Human Cortical Organoids with a Novel SCN2A Variant Exhibit Hyperexcitability and Differential Responses to Anti-Seizure Compounds.
Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies associated with channelopathy. Therefore, in the present study, we used a patient-derived organoid model with a novel SCN2A mutation (p.E512K) to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds. The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation. Immunofluorescence staining of patient-derived cortical organoids (COs) displayed normal neurodevelopment. Multielectrode array (MEA) recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts. Moreover, the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine. Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.
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[Are mini-brains watching you?].
iPSC-derived brain and retinal organoids represent biologically relevant 3D models. A new step in the field of brain and retinal organoids was reached a few months ago with the simultaneous development of brain and eye structures from human iPS cells within the same organoid. Single-cell mRNA sequencing analyses allowed the identification of various ocular and cerebral neuronal populations and electrophysiological recordings confirm the presence of functional and electrically active neurons. The coexistence within the same organoid of different cell types from visual and brain regions and the establishment of connections between these regions raise the intriguing question of its real or potential functionality and its ability to process higher-level visual information. This unique model could also be used to further understand the development of the human visual system and associated developmental diseases.
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Lysophosphatidic acid and sphingosine-1-phosphate are apical polarity cues in multiple organoid systems.
Apicobasal polarization is crucial for tissue organization during in vivo development and in human organoid models. Extracellular matrix (ECM) signaling typically provides a basal cue, and intestinal and lung organoids reverse polarity from apical-in to apical-out after ECM removal. However, ECM-free brain organoids maintain apical-in polarity, suggesting that media components may influence polarity. Exposing brain organoids to serum induced apical-out orientation. Lysophosphatidic acid (LPA), present in the medium of prior apical-out techniques, was identified as the causative factor. LPA-induced apical-out orientation in brain organoids occurred within 1 day, lasted at least 1 month, and was optimal at human cerebrospinal fluid LPA concentrations. Sphingosine-1-phosphate (S1P) induced similar apical-out polarization. Pharmacological studies revealed that LPA/S1P act via a G-protein coupled receptor/RhoA pathway. Finally, LPA induced apical-out polarity in patient-derived human lung and intestinal organoids, iPSC spheres, and multilineage iPSC-derived intestinal organoids. These findings indicate that LPA signaling is a critical apical polarity cue in multiple tissues.
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Advancing insights into virus-induced neurodevelopmental disorders through human brain organoid modelling.
Human neurodevelopment is a complex process vulnerable to disruptions, particularly during the prenatal period. Maternal viral infections represent a significant environmental factor contributing to a spectrum of congenital defects with profound and enduring impacts on affected offspring. The advent of induced pluripotent stem cell (iPSC)-derived three-dimensional (3D) human brain organoids has revolutionised our ability to model prenatal viral infections and associated neurodevelopmental disorders. Notably, human brain organoids provide a distinct advantage over traditional animal models, whose brain structures and developmental processes differ markedly from those of humans. These organoids offer a sophisticated platform for investigating viral pathogenesis, infection mechanisms and potential therapeutic interventions, as demonstrated by their pivotal role during the 2016 Zika virus outbreak. This review critically examines the utilisation of brain organoids in elucidating the mechanisms of TORCH viral infections, their impact on human brain development and contribution to associated neurodevelopmental disorders.