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Page 26 of 545-
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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A microglia-containing cerebral organoid model to study early life immune challenges.
Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.
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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.
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A Robust Methodological Framework for Generating Whole-Brain and Cortical Organoids From Diverse Healthy- and Patient-Derived Induced Pluripotent Stem Cell Lines.
BACKGROUND: Patient-derived neural organoids (NOs) have emerged as powerful tools for modeling human neurodevelopmental disorders, especially when animal models are unavailable or fail to recapitulate human-specific cortical development. However, significant variability in differentiation potential, even among healthy donor lines, and especially in fragile patient-derived induced pluripotent stem cells (iPSCs), poses major methodological challenges. Protocols that succeed in one line may fail in others, leading to poor organoid formation, reduced growth, impaired neuroepithelial patterning, or complete failure to generate neural tissues. METHODS: By systematically comparing multiple published protocols, we identified key sources of variability and ultimately developed optimized protocols for generating both whole-brain (WB) and cortical organoids (CO) from human iPSCs (hiPSCs), including lines from progeroid Cockayne syndrome patients. RESULTS: Through iterative refinement of critical parameters, including cell seeding density, Matrigel incorporation, and timing and type of pathway inhibition, we achieved consistent organoid growth and structural organization across all tested lines. The resulting pipeline is adaptable and can be further tailored for newly derived or particularly challenging hiPSC lines. CONCLUSION: Collectively, this methodological framework enables robust and reproducible generation of NOs from genetically diverse hiPSC sources, providing a reliable platform for studying human neurodevelopment and disease mechanisms in progeroid and other patient-specific contexts.
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A Comprehensive Update of Cerebral Organoids between Applications and Challenges.
The basic technology of stem cells has been developed and created organoids, which have established a strong interest in regenerative medicine. Different cell types have been used to generate cerebral organoids, which include interneurons and oligodendrocytes (OLs). OLs are fundamental for brain development. Abundant studies have displayed that brain organoids can recapitulate fundamental and vital features of the human brain, such as cellular regulation and distribution, neuronal networks, electrical activities, and physiological structure. The organoids contain essential ventral brain domains and functional cortical interneurons, which are similar to the developing cortex and medial ganglionic eminence (MGE). So, brain organoids have provided a singular model to study and investigate neurological disorder mechanisms and therapeutics. Furthermore, the blood brain barrier (BBB) organoids modeling contributes to accelerate therapeutic discovery for the treatment of several neuropathologies. In this review, we summarized the advances of the brain organoids applications to investigate neurological disorder mechanisms such as neurodevelopmental and neurodegenerative disorders, mental disorders, brain cancer, and cerebral viral infections. We discussed brain organoids' therapeutic application as a potential therapeutic unique method and highlighted in detail the challenges and hurdles of organoid models.
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Lessons about physiological relevance learned from large-scale meta-analysis of co-expression networks in brain organoids.
Integrative analysis of publicly available scRNA-seq data facilitates deeper understanding of biological phenomena with strong statistical power and high resolution. A new study in this issue of PLOS Biology examined the fidelity of various brain organoid protocols in reference to human primary developing brain by gene co-expression relationships with million-scale collection of public scRNA-seq data sets.