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Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection.
The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we describe optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions.
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Urgency with integrity: Why the profound autism community needs brain organoids now.
The profound autism community must support brain organoid research, and scientists must hurry up and build ethical guardrails so that this new technology can be put to work to improve lives.
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Cellular self-assembly and biomaterials-based organoid models of development and diseases.
UNLABELLED: Organogenesis and morphogenesis have informed our understanding of physiology, pathophysiology, and avenues to create new curative and regenerative therapies. Thus far, this understanding has been hindered by the lack of a physiologically relevant yet accessible model that affords biological control. Recently, three-dimensional ex vivo cellular cultures created through cellular self-assembly under natural extracellular matrix cues or through biomaterial-based directed assembly have been shown to physically resemble and recapture some functionality of target organs. These "organoids" have garnered momentum for their applications in modeling human development and disease, drug screening, and future therapy design or even organ replacement. This review first discusses the self-organizing organoids as materials with emergent properties and their advantages and limitations. We subsequently describe biomaterials-based strategies used to afford more control of the organoid's microenvironment and ensuing cellular composition and organization. In this review, we also offer our perspective on how multifunctional biomaterials with precise spatial and temporal control could ultimately bridge the gap between in vitro organoid platforms and their in vivo counterparts. STATEMENT OF SIGNIFICANCE: Several notable reviews have highlighted PSC-derived organoids and 3D aggregates, including embryoid bodies, from a development and cellular assembly perspective. The focus of this review is to highlight the materials-based approaches that cells, including PSCs and others, adopt for self-assembly and the controlled development of complex tissues, such as that of the brain, gut, and immune system.
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Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model.
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease. METHODS: In this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone's impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model. RESULTS: Tilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients.
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Towards a quality control framework for cerebral cortical organoids.
Cerebral organoids offer significant potential for neuroscience research as complex in vitro models that mimic human brain development. However, challenges related to their quality and reproducibility hinder their reliability. Discrepancies in morphology, size, cellular composition, and cytoarchitectural organization limit their applications, particularly in disease modeling, drug screening, and neurotoxicity testing. Critically, current methods for organoid characterization often lack standardization, restricting their broader applicability. To address the need for standardized quality assessment of cerebral organoids, we developed a Quality Control (QC) methodology for 60-day cortical organoids, evaluating five key criteria using a scoring system: morphology, size and growth profile, cellular composition, cytoarchitectural organization, and cytotoxicity. We implemented a hierarchical approach, beginning with non-invasive assessments to exclude low-quality organoids, while reserving in-depth analyses for those that passed the initial evaluation. To validate this framework, we exposed 60-day cortical organoids to graded doses of hydrogen peroxide (H2O2), inducing a range of quality outcomes. The QC system demonstrated its robustness by accurately discriminating organoid qualities. Our proposed QC framework is designed to be user-friendly, flexible, and broadly applicable, making it suitable for routine assessment of cerebral organoid quality. Additionally, its scalability enables industrial applications, offering a valuable tool for advancing both fundamental and pre-clinical research.
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Microfibrous Scaffolds Guide Stem Cell Lumenogenesis and Brain Organoid Engineering.
3D organoids are widely used as tractable in vitro models capable of elucidating aspects of human development and disease. However, the manual and low-throughput culture methods, coupled with a low reproducibility and geometric heterogeneity, restrict the scope and application of organoid research. Combining expertise from stem cell biology and bioengineering offers a promising approach to address some of these limitations. Here, melt electrospinning writing is used to generate tuneable grid scaffolds that can guide the self-organization of pluripotent stem cells into patterned arrays of embryoid bodies. Grid geometry is shown to be a key determinant of stem cell self-organization, guiding the position and size of emerging lumens via curvature-controlled tissue growth. Two distinct methods for culturing scaffold-grown embryoid bodies into either interconnected or spatially discrete cerebral organoids are reported. These scaffolds provide a high-throughput method to generate, culture, and analyze large numbers of organoids, substantially reducing the time investment and manual labor involved in conventional methods of organoid culture. It is anticipated that this methodological development will open up new opportunities for guiding pluripotent stem cell culture, studying lumenogenesis, and generating large numbers of uniform organoids for high-throughput screening.
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Convergence and innovative applications of cutting-edge biomedical technologies in brain organoid research.
Brain organoids, as three-dimensional cellular models that recapitulate human brain development and function in vitro, have emerged as a pivotal platform for neuroscience research. However, it still faces many technical challenges in aspects such as the structural and physiological relevance, functional regulation and system analysis, and urgently needs the deep integration of multi-disciplinary technologies to drive paradigm-shifting innovations. Here, we systematically summarize the main technological frameworks that support brain organoid research, including bioengineering and organoid construction technologies, biofabrication and microenvironmental modulation strategies, high-precision detection and multimodal analytical methodologies, as well as intelligent algorithms and data analysis platforms. The cross-integration of multiple technologies not only provides solutions to the existing limitations in brain organoid research, but also opens up cross-technological innovation application scenarios. We further discuss key bottlenecks in technology convergence and propose the development direction of future research. This review aims to provide a comprehensive technical roadmap for brain organoid research, promoting its in-depth application and paradigm innovation in cross-disciplinary fields including neuroscience, precision medicine, and brain-inspired computing.
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Lack of Transmission of Chronic Wasting Disease Prions to Human Cerebral Organoids.
Chronic wasting disease (CWD) is a cervid prion disease with unknown zoonotic potential that might pose a risk to humans who are exposed. To assess the potential of CWD to infect human neural tissue, we used human cerebral organoids with 2 different prion genotypes, 1 of which has previously been associated with susceptibility to zoonotic prion disease. We exposed organoids from both genotypes to high concentrations of CWD inocula from 3 different sources for 7 days, then screened for infection periodically for up to 180 days. No de novo CWD propagation or deposition of protease-resistant forms of human prions was evident in CWD-exposed organoids. Some persistence of the original inoculum was detected, which was equivalent in prion gene knockout organoids and thus not attributable to human prion propagation. Overall, the unsuccessful propagation of CWD in cerebral organoids supports a strong species barrier to transmission of CWD prions to humans.
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Dissecting the epigenetic regulation of human brain organoid development in single cells.
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Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons.
An inter-regional cortical tract is one of the most fundamental architectural motifs that integrates neural circuits to orchestrate and generate complex functions of the human brain. To understand the mechanistic significance of inter-regional projections on development of neural circuits, we investigated an in vitro neural tissue model for inter-regional connections, in which two cerebral organoids are connected with a bundle of reciprocally extended axons. The connected organoids produced more complex and intense oscillatory activity than conventional or directly fused cerebral organoids, suggesting the inter-organoid axonal connections enhance and support the complex network activity. In addition, optogenetic stimulation of the inter-organoid axon bundles could entrain the activity of the organoids and induce robust short-term plasticity of the macroscopic circuit. These results demonstrated that the projection axons could serve as a structural hub that boosts functionality of the organoid-circuits. This model could contribute to further investigation on development and functions of macroscopic neuronal circuits in vitro.