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Building brains in a dish: Prospects for growing cerebral organoids from stem cells.
The recent development of organoid techniques, in which embryonic brain-like tissue can be grown from human or mouse stem cells in vitro offers the potential to transform the way in which brain development is studied. In this review, we summarize key aspects of the embryonic development of mammalian forebrains, focussing in particular on the cerebral cortex and highlight significant differences between mouse and primates, including human. We discuss recent work using cerebral organoids that has revealed key similarities and differences between their development and that of the brain in vivo. Finally, we outline the ways in which cerebral organoids can be used in combination with CRISPR/Cas9 genome editing to unravel genetic mechanisms that control embryonic development of the cerebral cortex, how this can help us understand the causes of neurodevelopmental disorders and some of the key challenges which will have to be resolved before organoids can become a mainstream tool to study brain development.
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Protocol for generating in vitro glioma models using human-induced pluripotent- or embryonic-stem-cell-derived cerebral organoids.
In glioma modeling, existing organoid protocols lack the ability to replicate glioma cell invasion and interaction with normal brain tissue. Here, we present a protocol for generating in vitro brain disease models using human-induced pluripotent- or embryonic-stem-cell-derived cerebral organoids (COs). We describe steps for forming glioma organoids by co-culturing forebrain organoids with U-87 MG cells. We also detail vibratome sectioning of COs to prevent cell death and enhance contact between U-87 MG cells and cerebral tissues.
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Dishing out mini-brains: Current progress and future prospects in brain organoid research.
The ability to model human brain development in vitro represents an important step in our study of developmental processes and neurological disorders. Protocols that utilize human embryonic and induced pluripotent stem cells can now generate organoids which faithfully recapitulate, on a cell-biological and gene expression level, the early period of human embryonic and fetal brain development. In combination with novel gene editing tools, such as CRISPR, these methods represent an unprecedented model system in the field of mammalian neural development. In this review, we focus on the similarities of current organoid methods to in vivo brain development, discuss their limitations and potential improvements, and explore the future venues of brain organoid research.
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The neuro-immune-vascular landscape of lung cancer brain metastasis: insights from organoid models.
Lung cancer brain metastasis (LCBM) is a major cause of cancer-related mortality, driven by the restrictive blood-brain barrier (BBB), an immunosuppressive microenvironment, and dynamic metabolic reprogramming. Increasing evidence suggests that LCBM is governed by coordinated interactions among neural, immune, and vascular components that regulate metastatic colonization, progression, and immune evasion. However, conventional models fail to recapitulate this multicellular, spatially organized ecosystem, limiting mechanistic understanding. Recent advances in organoid technology provide a new paradigm for modeling LCBM. Integrative platforms, including cerebral organoid assembloids, vascularized microfluidic systems, and BBB models, enable reconstruction of key components and dynamic interactions within the brain metastatic niche. These systems have uncovered critical regulatory axes, such as astrocyte-driven colonization, neurovascular remodeling, and metabolic-immune coupling. Beyond structural modeling, organoid platforms enable functional interrogation of patient-specific therapeutic responses in physiologically relevant contexts, facilitating drug sensitivity testing, immunotherapy optimization, and multi-modal treatment modeling. Despite current limitations, organoid-based models provide a critical framework for dissecting the neuro-immune-vascular landscape of LCBM and bridging mechanistic insights with clinical translation, offering new opportunities for therapeutic innovation and personalized treatment.
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Sporadic Creutzfeldt-Jakob disease prion infection of human cerebral organoids.
For the transmissible, neurogenerative family of prion diseases, few human models of infection exist and none represent structured neuronal tissue. Human cerebral organoids are self-organizing, three-dimensional brain tissues that can be grown from induced pluripotent stem cells. Organoids can model aspects of neurodegeneration in Alzheimer's Disease and Down's Syndrome, reproducing tau hyperphosphorylation and amyloid plaque pathology. To determine whether organoids could be used to reproduce human prion infection and pathogenesis, we inoculated organoids with two sporadic Creutzfeldt-Jakob Disease prion subtypes. Organoids showed uptake, followed by clearance, of the infectious inoculum. Subsequent re-emergence of prion self-seeding activity indicated de novo propagation. Organoid health assays, prion titer, prion protein electrophoretic mobility and immunohistochemistry demonstrated inoculum-specific differences. Our study shows, for the first time, that cerebral organoids can model aspects of human prion disease and thus offer a powerful system for investigating different human prion subtype pathologies and testing putative therapeutics.
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Novel model of cortical-meningeal organoid co-culture system improves human cortical brain organoid cytoarchitecture.
Human cortical organoids (hCOs), derived from human induced pluripotent stem cells (iPSCs), provide a platform to interrogate mechanisms of human brain development and diseases in complex three- dimensional tissues. However, current hCO development methods lack important non-neural tissues, such as the surrounding meningeal layer, that have been shown to be essential for normal corticogenesis and brain development. Here, we first generated hCOs from a single rosette to create more homogenous organoids with consistent size around 250 µm by day 5. We then took advantage of a 3D co-culture system to encapsulate brain organoids with a thin layer of meningeal cells from the very early stages of cortical development. Immunostaining analysis was performed to display different cortical layer markers during different stages of development. Real-time monitoring of organoid development using IncuCyte displayed enhanced morphology and increased growth rate over time. We found that meningeal-encapsulated organoids illustrated better laminar organization by exhibiting higher expression of REELIN by Cajal-Retzius neurons. Presence of meningeal cells resulted in a greater expansion of TBR2 intermediate progenitor cells (IPCs), the deep cortical layer (CTIP2) and upper cortical layer (BRN2). Finally, meningeal-encapsulated organoids enhanced outer radial glial and astrocyte formation illustrated by stronger expression of HOPX and GFAP markers, respectively. This study presents a novel 3D co-culture platform to more closely mimic the in vivo cortical brain structure and enable us to better investigating mechanisms underlying the neurodevelopmental disorders during embryonic development.
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Comparative Multiomics Analysis of Cerebral Organoid-Derived Exosomes during Organoid Maturation.
Cerebral organoids derived from human pluripotent stem cells recapitulate key features of early brain development and provide a physiologically relevant model for neurogenesis. Exosomes secreted by these organoids carry bioactive cargo and offer a noninvasive means to monitor maturation and intercellular communication. We performed comprehensive multiomics profiling of exosomes collected from cerebral organoids at defined developmental stages to evaluate their utility as biomarkers of neuronal differentiation. Metabolomic analysis revealed a progressive decline in amino acids, including glutamic acid, consistent with increased metabolic demand during neurogenesis. Lipidomic and neurosteroid profiling showed dynamic increases in phosphatidylethanolamine and pregnenolone, reflecting synaptic membrane formation and signaling. Transcriptomic and proteomic analyses identified stage-specific neurodevelopmental signatures, with key markers mirroring those of parent organoids. Collectively, cerebral organoid-derived exosomes faithfully reflect organoid maturation and provide a robust platform for tracking in vitro brain development.
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Light-Induced Differentiation of Forebrain Organoids by NVOC-SAG.
Hedgehog signaling pathway shapes our body by regulating proliferation and differentiation of cells. The spatial and temporal distribution pattern of its ligands finely controls the activity of the Hedgehog pathway during development. To mimic the active regulation of Hedgehog pathway, we have developed a light-inducible Hedgehog signaling activator 6-nitroveratryloxy-carbonyl Smoothened agonist (NVOC-SAG). Here we describe a method to selectively induce ventral differentiation of human iPS cell-derived forebrain organoids in a light-dependent manner. This article describes preparation of NVOC-SAG, culture of iPS cell-derived forebrain organoids, light irradiation, and downstream analyses.
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Potential ethical problems with human cerebral organoids: Consciousness and moral status of future brains in a dish.
Human cerebral organoids (HCOs) are an in vitro model of early neural development, aimed at modelling and understanding brain development and neurological disorders. In just a few years there has been rapid and considerable progress in the attempt to create a brain model capable of showcasing the characteristics of the human brain. There are still strong limitations to address, including the absence of vascularization which makes it difficult to feed the central layers of the organoid. Nevertheless, some important features of the nervous system have recently been observed in cerebral organoids: they manifest electrical activity (i.e. communication between neurons), are sensitive to light stimulation and are able to connect to a spinal cord by sending impulses that make a muscle contract. Recent data show that cortical organoid network development at ten months resembles some preterm babies EEG patterns. Although cerebral organoids are not close to human brains so far due to their extremely simplified structure, this state of things gives rise to ethical concerns about the creation and destructive experimental use of human cerebral organoids. Particularly, one can wonder whether a human cerebral organoid could develop some degree of consciousness and whether, under certain conditions, it could acquire its own moral status with the related rights. In this article, I discuss the conditions under which HCOs could be granted their own moral status. For this purpose, I consider the hypothesis that HCOs might develop a primitive form of consciousness and investigate the ways in which it could be detected. In light of all this, I finally point out some cautionary measures that could be introduced into research on and with human cerebral organoids.
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Electrophysiological development and functional plasticity in dissociated human cerebral organoids across multiple cell lines.
Microelectrode arrays (MEAs) are increasingly used to profile the development of synchronized activity in neural organoids, yet no organoid study has reported on the consistency of electrophysiological development across cell lines. Here, we used dissociated neural organoids derived from six cell lines on MEAs to characterize functional synapse development using multiple parameters across time. The dissociated organoids demonstrated increasing functional connectivity and network activity over time across all cell lines and plasticity in response to synaptic-like stimulation. Like the organoids they were derived from, dissociated organoid cultures contained a diverse mixture of cell types. These results demonstrate that dissociated cerebral organoids can generate functional neurons, akin to primary neuronal cultures from brain tissue, providing a scalable model for studies of neurodevelopment and synaptic function. Consistent with unguided differentiation, we observed variability in activity parameters linked to donor cell line and batch effects, which must be considered in experimental design.