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A screen of brain organoids to study neurodevelopmental disease.
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Integrating brain organoids, meningeal immunity, and glymphatic dynamics: toward modeling neuroimmune clearance and crosstalk in disease.
The central nervous system has long been considered an immune-privileged organ, but discoveries about meningeal lymphatics, meningeal immune cells, cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange, and aquaporin-4 (AQP4)-associated glymphatic-like transport are reshaping our understanding of waste clearance and immune surveillance in the brain. However, there are obvious breaks in the current model system. Animal models possess complete circulatory and meningeal structures, but are limited by species differences, imaging depth, operability, and high throughput. Traditional two-dimensional (2D) culture and transwell models lack 3D brain parenchymal structure, low-speed fluid dynamics, and the meningeal immune microenvironment. This paper proposes the concept of "brain parenchyma-lymphoid-meningeal immune assembly chip", which integrates brain organoids containing neurons, astrocytes and microglia, CSF-like fluid derived from choroid plexus organoids, microfluidic lymphatic channels, and meningeal immune modules containing meningeal lymphatic endothelium, meningeal fibroblasts, macrophages, and dendritic cells. Currently, the various component technologies required for this platform are still at different stages of experimental maturity and have not yet been integrated into a single system. This review discusses existing issues such as the cellular composition of the brain parenchyma module, the engineering simulation of glymphatic dynamics, the reconstruction of the meningeal lymphatic and immune interface, disease applications, and validation standards. It also outlines a phased development roadmap to build a platform capable of tracking the continuous process of "pathological product generation-fluid clearance-meningeal immune sensing-inflammatory feedback" under simulated human brain conditions, providing new tools for mechanism analysis and drug screening in neurodegenerative diseases, brain injury, and neuro-immunological diseases.
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Assembling human brain organoids.
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The promises and challenges of human brain organoids as models of neuropsychiatric disease.
Neuropsychiatric disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ) and bipolar disorder (BPD) are of great societal and medical importance, but the complexity of these diseases and the challenges of modeling the development and function of the human brain have made these disorders difficult to study experimentally. The recent development of 3D brain organoids derived from human pluripotent stem cells offers a promising approach for investigating the phenotypic underpinnings of these highly polygenic disorders and for understanding the contribution of individual risk variants and complex genetic background to human pathology. Here we discuss the advantages, limitations and future applications of human brain organoids as in vitro models of neuropsychiatric disease.
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Modeling cell-cell interactions in the brain using cerebral organoids.
Until recently, a great amount of brain studies have been conducted in human post mortem tissues, cell lines and model organisms. These researches provided useful insights regarding cell-cell interactions occurring in the brain. However, such approaches suffer from technical limitations and inaccurate modeling of the tissue 3D cytoarchitecture. Importantly, they might lack a human genetic background essential for disease modeling. With the development of protocols to generate human cerebral organoids, we are now closer to reproducing the early stages of human brain development in vitro. As a result, more relevant cell-cell interaction studies can be conducted. In this review, we discuss the advantages of 3D cultures over 2D in modulating brain cell-cell interactions during physiological and pathological development, as well as the progress made in developing organoids in which neurons, macroglia, microglia and vascularization are present. Finally, we debate the limitations of those models and possible future directions.
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Nanoplastics exposure-induced mitochondrial dysfunction contributes to disrupted stem cell differentiation in human cerebral organoids.
Nanoplastics are ubiquitous in our daily lives, raising concerns about their potential impact on the human brain. Many studies reported that nanoplastics permeate the blood-brain barrier and influence cellular processes in mouse models. However, the neurotoxic effects of ingesting nanoplastics on human brain remain poorly understood. Here, we treated cerebral organoids with polystyrene nanoplastics to model the effects of nanoplastic exposure on human brain. Importantly, we found that mitochondria might be the significant organelles affected by polystyrene nanoplastics using immunostaing and RNA-seq analysis. Subsequently, we observed the increased cell death and decreased cell differentiation in our cerebral organoids. In conclusion, our findings shed insights on the mechanisms underlying the toxicity of nanoplastics on human brain organoids, providing an evaluation system in detection potential environmental toxicity on human brain.
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Cell diversity and network dynamics in photosensitive human brain organoids.
In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.
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Oxygen-induced stress reveals context-specific gene regulatory effects in human brain organoids.
The interaction between genetic variants and environmental stressors is key to understanding the mechanisms underlying neurological diseases. In this study, we use human brain organoids to explore how varying oxygen levels expose context-dependent gene regulatory effects. By subjecting a genetically diverse panel of 21 brain organoids to hypoxic and hyperoxic conditions, we identify hundreds of gene regulatory changes that are undetectable under baseline conditions, with 148 trait-associated genes showing regulatory effects only in response to oxygen stress. To capture more nuanced transcriptional patterns, we employ topic modeling, which reveals context-specific gene regulation linked to dynamic cellular processes and environmental responses, offering a deeper understanding of how gene regulation is modulated in the brain. These findings underscore the importance of genotype-environment interactions in genetic studies of neurological disorders and provide new insights into the hidden regulatory mechanisms influenced by environmental factors in the brain.
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Metabolic Assessment in Human Pluripotent Stem Cell-Derived Cerebral Organoids Using HR-MAS NMR Spectroscopy.
Brain metabolism is vital to healthy brain function and is often altered in disease; yet direct investigation in patients is challenging. Although animal models are commonly used for studying brain metabolism, their use is under increasing scrutiny due to concerns of animal welfare and model validity. Human pluripotent stem cell (hPSC)-derived cerebral organoids (COs) present a unique opportunity to model human brain developmental and neuropathological processes, allowing for detailed metabolic characterization via multiple approaches. Here, we applied high-resolution magic-angle spinning (HR-MAS) proton nuclear magnetic resonance (1H-NMR) spectroscopy to analyze metabolite levels in hPSC-derived COs, establishing a pipeline to study neurometabolic pathways in these engineered human brain tissues. We identified and quantified 17 metabolites in hPSC-derived COs at different stages of maturity. The high spectral quality (linewidth < 4 Hz, SNR > 65) allowed detection of metabolite levels in 85- to 312-day-old hPSC-derived COs, which exhibited a metabolic profile similar to human fetal brain, with key distinguishing features relative to human adult brain, including: elevated lactate levels; approximately equimolar glutamate and glutamine levels; low N-acetylaspartate levels; and an abundance of hypotaurine. In summary, this study presents direct metabolic assessment in intact COs via HR-MAS 1H-NMR spectroscopy. Our approach provides a platform for investigating human brain metabolism and its alteration in human brain models of neurodegeneration.
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USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids.
De novo variants in the ubiquitin-proteasome pathway are linked to autism spectrum disorder (ASD), yet their functional impact on neurodevelopment remains poorly understood. We investigated USP15, a deubiquitinating enzyme with rare damaging variants identified in individuals with ASD, using isogenic human iPSC-derived brain organoids and single-cell transcriptomics. USP15 mutant organoids showed genotype-dependent, progenitor-centered alterations during corticogenesis. Heterozygous organoids modeling haploinsufficiency displayed a shift toward later pseudotime states together with altered maturation and synaptic organization of deep-layer neurons. In contrast, homozygous organoids showed broader phenotypes, including mitotic suppression, aberrant HOX gene expression, and stress-response activation. Regulon analysis showed reduced activity of progenitor-associated regulons, including SOX2, NR2F1, and NR2F2, in heterozygous organoids, whereas homozygous organoids exhibited broader changes in transcriptional regulatory networks. Furthermore, USP15 mutant-associated gene expression patterns were significantly enriched for established ASD risk genes. Comparison with the mouse brain perturbation atlas showed that the transcriptional signature of the USP15 mutant showed notable overlap with those of Fezf2 and Foxp1 mutants, key regulators of deep-layer projection neuron identity. These findings characterize genotype-dependent neurodevelopmental phenotypes associated with reduced USP15 dosage and provide a human neural framework for investigating ASD-relevant developmental mechanisms in the context of a rare ubiquitin-pathway variant.