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GSK3ß inhibitor CHIR 99021 modulates cerebral organoid development through dose-dependent regulation of apoptosis, proliferation, differentiation and migration.
Cerebral organoids generated from human pluripotent stem cells (hiPSCs) are unique in their ability to recapitulate human-specific neurodevelopmental events. They are capable of modeling the human brain and its cell composition, including human-specific progenitor cell types; ordered laminar compartments; and both cell-specific transcriptional signatures and the broader telencephalic transcriptional landscape. The serine/threonine kinase, GSK3β, plays a critical role in neurodevelopment, controlling processes as varied as neurogenesis, morphological changes, polarization, and migration. In the generation of cerebral organoids, inhibition of GSK3β at low doses has been used to increase organoid size and decrease necrotic core. However, little is known of the effects of GSK3β inhibition on organoid development. Here, we demonstrate that while low dose of GSK3β inhibitor CHIR 99021 increases organoid size, higher dose actually reduces organoid size; with the highest dose arresting organoid growth. To examine the mechanisms that may contribute to the phenotypic size differences observed in these treatment groups, we show that low dose of CHIR 99021 increases cell survival, neural progenitor cell proliferation and neuronal migration. A higher dose, however, decreases not only apoptosis but also proliferation, and arrests neural differentiation, enriching the pool of neuroepithelial cells, and decreasing the pools of early neuronal progenitors and neurons. These results reveal new mechanisms of the pleiotropic effects of GSK3β during organoid development, providing essential information for the improvement of organoid production and ultimately shedding light on the mechanisms of embryonic brain development.
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Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes.
Dysregulation of early neurodevelopment is implicated in macrocephaly/autism disorders. However, the mechanism underlying this dysregulation, particularly in human cells, remains poorly understood. Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, autism spectrum disorder (ASD), and intellectual disability. The in vivo roles of RAB39b in the brain remain unknown. We generated Rab39b knockout (KO) mice and found that they exhibited cortical neurogenesis impairment, macrocephaly, and hallmark ASD behaviors, which resembled patient phenotypes. We also produced mutant human cerebral organoids that were substantially enlarged due to the overproliferation and impaired differentiation of neural progenitor cells (NPCs), which resemble neurodevelopmental deficits in KO mice. Mechanistic studies reveal that RAB39b interacts with PI3K components and its deletion promotes PI3K-AKT-mTOR signaling in NPCs of mouse cortex and cerebral organoids. The mTOR activity is robustly enhanced in mutant outer radial glia cells (oRGs), a subtype of NPCs barely detectable in rodents but abundant in human brains. Inhibition of AKT signaling rescued enlarged organoid sizes and NPC overproliferation caused by RAB39b mutations. Therefore, RAB39b mutation promotes PI3K-AKT-mTOR activity and alters cortical neurogenesis, leading to macrocephaly and autistic-like behaviors. Our studies provide new insights into neurodevelopmental dysregulation and common pathways associated with ASD across species.
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Single cell RNA sequencing and emerging transcriptomic technologies in Alzheimer's disease cerebral organoids: a mini review.
Alzheimer's disease (AD), the most common cause of dementia worldwide, presents a formidable challenge due to its complex, multifactorial etiology, and limited translational success of existing models. Recent advances in stem cell biology have enabled the generation of three-dimensional human cerebral organoids which exhibit multicellular complexity and self-organisation, recapitulating key aspects of fetal brain development in vitro. This mini review highlights the landscape of AD modelling in human cerebral organoids. While studies using single cell RNA sequencing (scRNA-seq) form the core of this review, we also discuss single-nucleus RNA sequencing, computational deconvolution, and spatial approaches as translationally relevant extensions. We categorise current organoid research into distinct model types: (1) familial AD models driven by APP, PSEN1, and PSEN2 mutations; (2) sporadic AD models incorporating genetic APOE variants and environmental risk factors (serum exposure, pollutants, and viral reactivation); (3) tauopathy models highlighting astrocyte-driven metabolic disruption; (4) models featuring glial-immune interactions; and (5) emerging models of mitochondrial dysfunction as an early disease initiator. Across these categories, single cell technologies reveal critical alterations in lipid metabolism, synaptic programs, and glial-immune crosstalk. Finally, we review methodological innovations-drawing on non-AD developmental organoid studies such as region-specific patterning, morphodynamic control, and enhanced cellular diversity, which offer a roadmap for improving the physiological fidelity of next-generation AD organoid models. Ultimately, integrating these advanced cerebral organoid platforms with single cell technologies offer a powerful toolkit to dissect early disease mechanisms and accelerate the development of personalised therapeutics.
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Lab-grown 'mini brains' produce electrical patterns that resemble those of premature babies.
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The pathophysiology of neurological risk from environmental toxins: Microcystin-LR leads to a decrease in neuron count via the pyroptosis pathway using brain organoid models and mouse models.
The presence of microcystin-LR (MC-LR) poses a grave threat to both ecosystems and public health. Some studies have indicated that MC-LR can result in neurotoxicity, yet the specific mechanisms and effects remain unclear. This research used brain organoid models and mouse models to investigate the neurotoxic effects and mechanisms associated with MC-LR exposure. Findings from microelectrode array (MEA) assessments demonstrated a statistically significant reduction in both discharge activity and the number of neurons in the cerebral organoid upon acute exposure to MC-LR (P < 0.05). TUNEL (TdT-mediated dUTP nick end labeling) staining indicated that MC-LR exposure led to neuronal death and reduced neuron numbers in brain organoids. Meanwhile, the exposure of 12-month-old mice to low concentrations of MC-LR (0, 1, 60, and 120 μg/L) was found to lead to a decrease in the number of neurons based on histopathological and biochemical analyses. Moreover, long-term exposure to MC-LR also activated the JNK/NF-κB signaling pathway in the hippocampal region of the mouse brain tissue. The qPCR analysis demonstrated increased expression levels of the inflammatory markers nlrp3, caspase-1, il-18, il-6, and the pyroptosis-related marker gsdmd in hippocampal neuron tissue from groups exposed to 60 μg/L and 120 μg/L of MC-LR in mice. These results are consistent with those of the Western blot analysis. This study elucidated that prolonged exposure to MC-LR triggered activation of the JNK/NF-κB signaling pathway, neuroinflammation, neuronal pyroptosis.
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Effects of minocycline and rapamycin in gamma-irradiated human embryonic stem cells-derived cerebral organoids.
Radiation induces DNA and protein damage and free radical formation, effectively establishing cellular senescence in a variety of models. We demonstrate the effects of two known pleiotropic drugs following gamma radiation damage in neurosphere/cerebral organoid system based on human embryonic stem cells. mTORC1 repression by rapamycin prior to irradiation, or metabolic activation by minocycline after irradiation, partially rescues neuroepithelium integrity, neurite-growing capacity, ventricle formation and extracellular acidification rate as an integral measure of metabolic output. Cerebral organoid model thus provides valid and robust readouts for radiation studies in a complex 3D setting.
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Millifluidic triMEA organoid platform with stretchable microelectrode arrays for parallel organoid electrophysiology under standardized perfusion.
Organoids enable rigorous studies of neurodevelopment and disease, yet existing platforms often compromise between precise microenvironment control and reliable electrophysiological measurement. The challenge of achieving uniform perfusion alongside multi-well volumetric neural recordings limits parallel functional characterization and technical reproducibility across samples. Here, we present the triMEA millifluidic platform, which integrates three stretchable microelectrode arrays within a single device and delivers uniform perfusion across three independent wells. A single inlet supplies identical perfusion to each well, which stabilizes flow patterns and equalizes mechanical stimuli between chambers. This design facilitates simultaneous, independent electrophysiological recordings from three organoids within a single experimental setup. Using human midbrain organoids as a proof-of-concept biological model, we provide computational and experimental validation of the fluidic profiles and demonstrate electrophysiological recordings across all three wells under continuous perfusion. This platform establishes a reproducible and standardized foundation for parallel organoid interfacing.
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Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.
The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.
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Design and prototyping of a chip-based multi-micro-organoid culture system for substance testing, predictive to human (substance) exposure.
Dynamic miniaturized human multi-micro-organ bioreactor systems are envisaged as a possible solution for the embarrassing gap of predictive substance testing prior to human exposure. A rational approach was applied to simulate and design dynamic long-term cultures of the smallest possible functional human organ units, human "micro-organoids", on a chip the shape of a microscope slide. Each chip contains six identical dynamic micro-bioreactors with three different micro-organoid culture segments each, a feed supply and waste reservoirs. A liver, a brain cortex and a bone marrow micro-organoid segment were designed into each bioreactor. This design was translated into a multi-layer chip prototype and a routine manufacturing procedure was established. The first series of microscopable, chemically resistant and sterilizable chip prototypes was tested for matrix compatibility and primary cell culture suitability. Sterility and long-term human cell survival could be shown. Optimizing the applied design approach and prototyping tools resulted in a time period of only 3 months for a single design and prototyping cycle. This rapid prototyping scheme now allows for fast adjustment or redesign of inaccurate architectures. The designed chip platform is thus ready to be evaluated for the establishment and maintenance of the human liver, brain cortex and bone marrow micro-organoids in a systemic microenvironment.
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Case of granular-cell myoblastoma (organoid type) involving arm, lung, and brain, with twenty years' survival.