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Patient-derived glioma organoids real time identification of IDH mutation, 1p/19q-codeletion and CDKN2A/B homozygous deletion with differential ion mobility spectrometry.
PURPOSE: Extent of brain tumor resection continues to be one of the central decisions taken during standard of care in glioma patients. Here, we aimed to evaluate the most essential molecular factors, such as IDH (isocitrate dehydrogenase) mutation in gliomas classification with patient-derived glioma organoids (PGOs) using differential mobility spectrometry (DMS). METHODS: we prospectively recruited 12 glioma patients, 6 IDH-mutated and 6 IDH wild-type tumors, from which PGOs were generated ex-vivo. Altogether, 320 PGOs DMS spectra were analyzed with a classifier algorithm based on linear discriminant analysis (LDA). RESULTS: LDA model classification accuracy (CA) obtained between IDH-mutant and IDH wild-type PGOs was 90% (91% sensitivity and 89% specificity). Furthermore, 1p/19q codeletion classification within IDH mutant PGOs reached 98% CA (93% sensitivity and 99% specificity), while CDKN2A/B homozygous loss status had 86% CA (63% sensitivity 93% specificity). CONCLUSION: DMS suitability to differentiate IDH-mutated PGOs was thus validated in ex vivo cultured samples, PGOs. Preliminary results regarding 1p/19q codeleted PGOs and CDKN2A/B loss PGOs identification endorse testing in a prospective intraoperative glioma patient cohort. Our results reveal a sample classification set-up that is compatible with real-time intraoperative surgery guidance.
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Elastic Thermoplastic Polyurethane/Graphene Microneedle-Mesh Interfaces via Microfluidic Patterning for Electrophysiology in Neural Organoids.
Connecting electronics to the brain and neural organoids is critical for establishing machine-human interfaces, exploring complex mechanisms of the nervous system, and developing theranostic approaches. However, electrophysiological monitoring of these three-dimensional (3D) nervous tissues remains challenging due to their highly irregular surfaces, which severely limit electrode-tissue contact. Here, we present a stretchable mesh electrode array integrated with elastic graphene microneedles for interfacing with human neural organoids and their assemblies. The device is fabricated via microfluidic patterning technology, enabling low-cost and reproducible production. Graphene microneedles (50-100 μm in height) seamlessly interconnected with liquid metal-polymer conductor (MPC) interconnects within the stretchable mesh architecture. Graphene microneedles and MPC interconnects retain structural integrity under 200% strain. This configuration enhances multisite electrode-tissue contact, enabling recordings of spontaneous and stimulus-evoked electrophysiological activity. Over 60% of channels were activated, surpassing the performance of commercial planar electrodes. This biocompatible interface overcomes the mechanical mismatch between flexible electronics and the surface irregularities of neural organoids, providing an avenue for investigating emergent neural network behaviors in 3D models.
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Mapping the developmental trajectory of human astrocytes reveals divergence in glioblastoma.
Glioblastoma (GBM) is defined by heterogeneous and resilient cell populations that closely reflect neurodevelopmental cell types. Although it is clear that GBM echoes early and immature cell states, identifying the specific developmental programmes disrupted in these tumours has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly 2 years. Through this approach, we chronicled a multiphase developmental process. Our time course of human astrocyte maturation includes a molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wild-type neoplastic astrocyte-lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumour astrocyte-lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D-2-hydroxyglutarate oncometabolite exposure. We propose that this defiance is a consequence of IDH1-mutant-associated epigenetic dysregulation, and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a distinct cellular state aberration in GBM astrocyte-lineage cells and presents developmental targets for experimental and therapeutic exploration.
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Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer's tau pathology.
The apolipoprotein E4 (APOE4) genotype is one of the strongest genetic risk factors for Alzheimer's disease (AD), and is generally believed to cause widespread pathological alterations in various types of brain cells. Here, we developed a novel engineering method of creating the chimeric human cerebral organoids (chCOs) to assess the differential roles of APOE4 in neurons and astrocytes. First, the astrogenic factors NFIB and SOX9 were introduced into induced pluripotent stem cells (iPSCs) to accelerate the induction of astrocytes. Then the above induced iPSCs were mixed and cocultured with noninfected iPSCs under the standard culturing condition of cerebral organoids. As anticipated, the functional astrocytes were detected as early as 45 days, and it helped more neurons matured in chCOs in comparation of the control human cerebral organoids (hCOs). More interestingly, this method enabled us to generate chCOs containing neurons and astrocytes with different genotypes, namely APOE3 or APOE4. Then, it was found in chCOs that astrocytic APOE4 already significantly promoted lipid droplet formation and cholesterol accumulation in neurons while both astrocytic and neuronal APOE4 contributed to the maximum effect. Most notably, we observed that the co-occurrence of astrocytic and neuronal APOE4 were required to elevate neuronal phosphorylated tau levels in chCOs while Aβ levels were increased in chCOs with neuronal APOE4. Altogether, our results not only revealed the essence of both neuronal and astrocytic APOE4 for tau pathology, but also suggested chCOs as a valuable pathological model for AD research and drug discovery.
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Comment on "Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment".
Trujillo et al. (Research Articles, 12 February 2021, eaax2537) conclude that the reintroduction of an ancestral amino acid substitution in the protein NOVA1 drastically alters the development of brain organoids. We show that cell lines used by the authors carry heterozygous deletions of the target DNA sequence, providing another plausible explanation for the effects observed.
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Ultrastructural findings in medulloepitheliomatous neoplasms induced by human adenovirus 12 in rodents.
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Evaluation of ex vivo drug combination optimization platform in recurrent high grade astrocytic glioma: An interventional, non-randomized, open-label trial protocol.
INTRODUCTION: High grade astrocytic glioma (HGG) is a lethal solid malignancy with high recurrence rates and limited survival. While several cytotoxic agents have demonstrated efficacy against HGG, drug sensitivity testing platforms to aid in therapy selection are lacking. Patient-derived organoids (PDOs) have been shown to faithfully preserve the biological characteristics of several cancer types including HGG, and coupled with the experimental-analytical hybrid platform Quadratic Phenotypic Optimization Platform (QPOP) which evaluates therapeutic sensitivity at a patient-specific level, may aid as a tool for personalized medical decisions to improve treatment outcomes for HGG patients. METHODS: This is an interventional, non-randomized, open-label study, which aims to enroll 10 patients who will receive QPOP-guided chemotherapy at the time of first HGG recurrence following progression on standard first-line therapy. At the initial presentation of HGG, tumor will be harvested for primary PDO generation during the first biopsy/surgery. At the point of tumor recurrence, patients will be enrolled onto the main study to receive systemic therapy as second-line treatment. Subjects who undergo surgery at the time of recurrence will have a second harvest of tissue for PDO generation. Established PDOs will be subject to QPOP analyses to determine their therapeutic sensitivities to specific panels of drugs. A QPOP-guided treatment selection algorithm will then be used to select the most appropriate drug combination. The primary endpoint of the study is six-month progression-free survival. The secondary endpoints include twelve-month overall survival, RANO criteria and toxicities. In our radiological biomarker sub-study, we plan to evaluate novel radiopharmaceutical-based neuroimaging in determining blood-brain barrier permeability and to assess in vivo drug effects on tumor vasculature over time. TRIAL REGISTRATION: This trial was registered on 8th September 2022 with ClinicalTrials.gov Identifier: NCT05532397.
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Effect of temperature on the rapid retrograde transport of microscopically visible intra-axonal organelles.
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Integrative functional optical imaging approaches: Optics, microfluidics, and machine learning for neuroscience in organoids and small-animal models.
Advances in functional imaging have transformed neuroscience, enabling real-time mapping of neural activity and cellular dynamics. Techniques such as light-sheet microscopy allow whole-brain recordings in model organisms like Caenorhabditis elegans and zebrafish, revealing mechanisms of sensorimotor processing, learning, and neural circuit formation. More recently, the vast complexity of these datasets necessitates machine-learning tools for efficient analysis. Machine-learning-driven approaches improve data quality through denoising, automate segmentation of neurons and tissues, and enable analyses on complex data. By integrating machine learning with advanced imaging, researchers can decode developmental trajectories and neural-network function with unprecedented precision. This review explores the synergy between imaging and computation, highlighting how these innovations drive discoveries in neuroscience.
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Intracerebral Ganglioneuroblastoma with intracytoplasmic microtubular aggregates: case report and ultrastructural study.
Cerebral ganglioneuroblastoma is a rare entity that is not well characterized at the ultrastructural level. We report a case of such a neoplasm with some unique fine structural features. The tumor contains both small cells with little evidence of differentiation and large, bizarre multinucleate cells, many of which contain intracytoplasmic aggregates of 22- to 24-nm microtubules that displace the nucleus and cytoplasmic organelles to the periphery of the cell. Inclusions of this type have of previously been described in this entity.