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Intermittent Propofol Exposure Induces Neurodevelopmental Alterations in Human Brain Organoids.
The administration of anaesthesia during pregnancy may have implications for fetal brain development. This study used H1 embryonic stem cell-derived human brain organoids (HBOs) to investigate effects of intermittent propofol exposure (IPE). HBOs were subjected to early IPE from 47 to 50 days in vitro (div), or late IPE from 77 to 80 div, using a clinically supra-anaesthetic concentration of 50 µM propofol. This was followed by cultivation without propofol for an additional 10 div, and HBOs were subsequently analysed at 60 or 90 div. Determination of HBO growth and lactate release did not provide evidence of neurotoxicity. Multi-electrode array recordings indicated an increased neuronal activity at 60 div following early IPE, an effect not observed at 90 div following late IPE. RNA-sequencing revealed that IPE up-regulated genes associated with neurodevelopment and synapse functions at 60 div, which overlapped with naturally up-regulated genes during HBO development from 60 to 90 div. These findings indicate that early IPE accelerates brain maturation in HBOs, suggesting possible deviations from the normal developmental trajectory in the fetal brain.
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Cellular complexity in brain organoids: Current progress and unsolved issues.
Brain organoids are three-dimensional neural aggregates derived from pluripotent stem cells through self-organization and recapitulate architectural and cellular aspects of certain brain regions. Brain organoids are currently a highly exciting area of research that includes the study of human brain development, function, and dysfunction in unprecedented ways. In this Review, we discuss recent discoveries related to the generation of brain organoids that resemble diverse brain regions. We provide an overview of the strategies to complement these primarily neuroectodermal models with cell types of non-neuronal origin, such as vasculature and immune cells. Recent transplantation approaches aiming to achieve higher cellular complexity and long-term survival of these models will then be discussed. We conclude by highlighting unresolved key questions and future directions in this exciting area of human brain organogenesis.
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Modeling human brain development with cerebral organoids.
The recent discovery of a new three-dimensional culture system for the derivation of cerebral organoids from human induced pluripotent stem cells provides developmental neurobiologists with the first example of a three-dimensional framework for the study of human brain development. This innovative approach permits the in vitro assembly of a human embryonic brain rudiment that recapitulates the developing human cerebrum. Organoids contain progenitor populations that develop to yield mature cortical neuron subtypes, potentially allowing investigators to study complex brain diseases that lack appropriate animal models.
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Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure.
Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.
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Protocol for cryopreserving neural organoids and human living brain tissue using MEDY.
Cryopreservation of neural organoids and human living brain tissue faces huge challenges. Here, we present a cryopreservation protocol for the reliable storage of diverse neural organoids and human living brain tissue using methylcellulose, ethylene glycol, DMSO, and Y27632, termed MEDY. We describe steps for preparing cryopreservation solution, preparing cortical organoids, and surgical removal of human brain tissue. We then detail procedures for cryopreservation, resuscitation, and detection assays. This protocol can serve as a model for studying human neurological diseases. For complete details on the use and execution of this protocol, please refer to Xue et al.1.
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Vascularization of human brain organoids.
Human brain organoids are three-dimensional tissues that are generated in vitro from pluripotent stem cells and recapitulate the early development of the human brain. Brain organoids consist mainly of neural lineage cells, such as neural stem/precursor cells, neurons, astrocytes, and oligodendrocytes. However, all human brain organoids lack vasculature, which plays indispensable roles not only in brain homeostasis but also in brain development. In addition to the delivery of oxygen and nutrition, accumulating evidence suggests that the vascular system of the brain regulates neural differentiation, migration, and circuit formation during development. Therefore, vascularization of human brain organoids is of great importance. Current trials to vascularize various organoids include the adjustment of cultivation protocols, the introduction of microfluidic devices, and the transplantation of organoids into immunodeficient mice. In this review, we summarize the efforts to accomplish vascularization and perfusion of brain organoids, and we discuss these attempts from a forward-looking perspective.
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iPSCs-Derived Neurons and Brain Organoids from Patients.
Induced pluripotent stem cells (iPSCs) can be differentiated into specific neurons and brain organoids by adding induction factors and small molecules in vitro, which carry human genetic information and recapitulate the development process of human brain as well as physiological, pathological, and pharmacological characteristics. Hence, iPSC-derived neurons and organoids hold great promise for studying human brain development and related nervous system diseases in vitro, and provide a platform for drug screening. In this chapter, we summarize the development of the differentiation techniques for neurons and brain organoids from iPSCs, and their applications in studying brain disease, drug screening, and transplantation.
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Spatial Neurobiology in Brain Organoids Using Mass Spectrometry Imaging-Based Multiomics Approach.
Brain organoids are stem cell-derived, three-dimensional models that more accurately mimic the cellular complexity and architecture of human brain tissues compared to traditional two-dimensional (2D) cultures or animal models. Their physiological relevance and human-specific neurobiology enhance translational research while aligning with current regulatory shifts toward reducing animal testing in biomedical science. A thorough understanding of the molecular landscape of various biomolecules, such as lipids, metabolites, proteins, and glycans in physiologically relevant brain models, such as organoids, is essential to deciphering complex neurobiology. While mass spectrometry has long been used to understand such molecular landscape in tissues, a single-omics approach is insufficient to fully capture the complexity of brain biology. Therefore, multiomics strategies, such as high-resolution mass spectrometry imaging (MSI), mass spectrometry-based proteomics, and lipidomics, together can provide a holistic view of biomolecular interplay within tissue microenvironments. Moreover, since MSI retains spatial information within tissues, MSI-based multiomics approaches hold immense potential to uncover complex neurobiology within brain organoids. In this article, we present our perspectives on leveraging MSI-based multiomics in brain organoids to understand the complex molecular interplay underlying neurobiology.
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Bezafibrate treatment rescues neurodevelopmental and neurodegenerative defects in 3D cortical organoid model of MAPT frontotemporal dementia.
INTRODUCTION: The intronic MAPT mutation IVS10+16 is linked to familial frontotemporal dementia, causing hyperphosphorylation and accumulation of tau protein, resulting in synaptic and neuronal loss and neuroinflammation in patients. This mutation disrupts MAPT gene splicing, increasing exon 10 inclusion and leading to an imbalance of 3R and 4R Tau isoforms. METHODS: We generated patterned cortical organoids from isogenic control and mutant human induced pluripotent stem cell (iPSC) lines. Nanostring gene expression analysis, immunofluorescence, and calcium imaging recordings were used to study the impact of the MAPT IVS10+16 mutation on neuronal development and function. RESULTS: Tau mutant cortical organoids showed altered mitochondrial function and gene expression related to neuronal development, with synaptic markers and neuronal activity reduction. Bezafibrate treatment restored mitochondrial content and rescued synaptic functionality and tau physiology. DISCUSSION: These findings suggest that targeting mitochondrial function with bezafibrate could potentially reverse tau-induced neurodevelopmental deficits, highlighting its therapeutic potential for tauopathies like frontotemporal dementia. HIGHLIGHTS: The IVS 10+16 MAPT mutation significantly disrupts cortical differentiation and synaptic maturation, evidenced by downregulated genes associated with synapses and neuronal development. Tau-mutant cortical organoids exhibit mitochondrial dysfunction, with fewer and smaller mitochondria alongside tau hyperphosphorylation and aggregation, which further contribute to neuronal damage and disease progression. Treatment with bezafibrate effectively normalizes mitochondrial parameters, enhances neuronal integrity and synaptic maturation, and restores network functionality, showcasing its promise as a therapeutic strategy for tauopathies. The 3D in vitro disease model used in this study proves valuable for studying tauopathies and testing new drugs, effectively mimicking key aspects of tau-related neurodegeneration.
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Analysis of Synapses in Cerebral Organoids.
Cerebral organoids are an emerging cutting-edge technology to model human brain development and neurodevelopmental disorders, for which mouse models exhibit significant limitations. In the human brain, synaptic connections define neural circuits, and synaptic deficits account for various neurodevelopmental disorders. Thus, harnessing the full power of cerebral organoids for human brain modeling requires the ability to visualize and analyze synapses in cerebral organoids. Previously, we devised an optimized method to generate human cerebral organoids, and showed that optimal organoids express mature-neuron markers, including synaptic proteins and neurotransmitter receptors and transporters. Here, we give evidence for synaptogenesis in cerebral organoids, via microscopical visualization of synapses. We also describe multiple approaches to quantitatively analyze synapses in cerebral organoids. Collectively, our work provides sufficient evidence for the possibility of modeling synaptogenesis and synaptic disorders in cerebral organoids, and may help advance the use of cerebral organoids in molecular neuroscience and studies of neurodevelopmental disorders such as autism.