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Three-dimensional microfluidics with dynamic fluidic perturbation promotes viability and uniformity of human cerebral organoids.
Human cerebral organoids (COs), generated from stem cells, are emerging animal alternatives for understanding brain development and neurodegeneration diseases. Long-term growth of COs is currently hindered by the limitation of efficient oxygen infiltration and continuous nutrient supply, leading to general inner hypoxia and cell death at the core region of the organoids. Here, we developed a three-dimensional (3D) microfluidic platform with dynamic fluidic perturbation and oxygen supply. We demonstrated COs cultured in the 3D microfluidic system grew continuously for over 50 days without cell death at the core region. Increased cell proliferation and enhanced cell differentiation were also observed and verified with immunofluorescence staining, proteomics and metabolomics. Time-lapse proteomics from 7 consecutive acquisitions between day 4 and day 30 identified 546 proteins differently expressed accompanying COs growth, which were mainly relevant to nervous system development, in utero embryonic development, brain development and neuron migration. Our 3D microfluidic platform provides potential utility for culturing high-homogeneous human organoids.
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Sialic acid in crude myelin fractions from rat brain.
Protein- and lipid-bound sialic acid was assayed in myelin fractions isolated by four different methods from rat brain homogenates. The extent to which non-myelin cellular membranes contaminate these fractions was assessed by electron microscopy and marker-enzyme assays. Small amounts of sialic acid found in the least contaminated myelin fractions are considered to be constituents of axonal and satellite cell plasma membranes known to be present. The data are discussed with reference to the ultrastructural appearance of myelin.
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Establishing a living biobank of pediatric high-grade glioma and ependymoma suitable for cancer pharmacology.
BACKGROUND: Brain tumors are the deadliest solid tumors in children and adolescents. Most of these tumors are glial in origin and exhibit strong heterogeneity, hampering the development of effective therapeutic strategies. In the past decades, patient-derived tumor organoids (PDT-O) have emerged as powerful tools for modeling tumoral cell diversity and dynamics, and they could then help define new therapeutic options for pediatric brain tumors. METHODS: Through an integrative approach based on our expertise and a careful review of the literature about glioblastoma 3D primary cultures, we set up a standardized methodological pipeline for the establishment, characterization, and biobanking of PDT-O through direct 3D in vitro culture of the deadliest pediatric glial brain tumors. To assess PDT-O fidelity and validate their preclinical relevance, we performed comprehensive histological, molecular, and drug-response analyses. RESULTS: Our methodological pipeline allowed the rapid and efficient generation of PDT-O recapitulating their parental tumor features, including intratumoral heterogeneity, even after several passages and cryopreservation/revival as 3D cultures. Moreover, we successfully performed preclinical test responses on these PDT-O to standard-of-care therapies and new therapeutic options. Finally, we identified ONC201 as a selective drug for pediatric glial tumor types not restricted to H3K27-altered glial tumors, as well as combination strategies to increase the therapeutic response to ONC201. CONCLUSIONS: Hence, we describe a fast and robust process to biobank PDT-O for pediatric glial brain tumors. These PDT-O models have the potential for patient-specific modeling even after long-term expansion in vitro, and we established the proof-of-concept of their usefulness to support powerful preclinical studies.
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Cholinergic neuron-to-glioblastoma synapses in a human iPSC-derived co-culture model.
Glioblastoma (GBM) integrates extensively into brain-wide neuronal circuits; however, neuron-tumor interactions have largely been studied with glutamatergic neurons in animal models. The role of neuromodulatory circuits for GBM biology in all-human cell systems remains unclear. Here, we report a co-culture system employing patient-derived GBM organoids and human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons. We provided evidence of structural human cholinergic synaptic inputs onto GBM cells via trans-monosynaptic tracing and electron microscopy and functional synaptic interactions through the metabotropic CHRM3 receptor via calcium imaging. Deep single-cell RNA sequencing of co-cultures compared to GBM monocultures further revealed shifts in tumor transcriptional profiles toward a more proliferative state, with contributions from both diffusible factors and direct contacts, the latter of which are dependent on cholesterol biosynthesis. Together, our findings support the role of cholinergic inputs in promoting GBM progression and highlight hiPSC-derived co-culture models as a useful platform for cancer neuroscience.
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Fine structure of primary reticulum cell sacroma of the brain.
An electron microscopic study was made on two cases of reticulum cell sarcoma (microglioma) of the brain. In both, the tumour was composed of several type of cells; cells with an undifferentiated appearance and cells with ultrastructural features of the reticulum cell and histiocyte. There seemed to be no significant difference in the fine structure between the tumour cells in reticulum cell sarcoma of the brain and extracerebral forms. The ultrastructures of a lymphosarcoma of the spinal epidural space was also examined and resembles that of such tumours occurring elsewhere in the body.
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In a century from agitated cells to human organoids.
Reaching back more than a century, suspension cultures have provided major insights into processes of histogenesis; e.g., cell communication, distinction of self/nonself, cell sorting and cell adhesion. Besides studies on lower animals, the vertebrate retina served as excellent reaggregate model to analyze 3D reconstruction of a complex neural laminar tissue. Methodologically, keeping cells under suspension is essential to achieve tissue organisation in vitro; thereby, the environmental conditions direct the emergent histotypic particulars. Recent progress in regenerative medicine is based to a large extent on human induced pluripotent stem cells (hiPSCs), which are cultured under suspension. Following their genetically directed differentiation into various histologic 3D structures, organoids provide excellent multipurpose in vitro assay models, as well as tissues for repair transplantations. Historically, a nearly fully laminated retinal spheroid from avian embryos was achieved already in 1984, foreshadowing the potential of culturing stem cells under suspension for tissue reconstruction purposes.
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Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT.
Dimethyltryptamines are entheogenic serotonin-like molecules present in traditional Amerindian medicine recently associated with cognitive gains, antidepressant effects, and changes in brain areas related to attention. Legal restrictions and the lack of adequate experimental models have limited the understanding of how such substances impact human brain metabolism. Here we used shotgun mass spectrometry to explore proteomic differences induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico analysis reinforced previously reported anti-inflammatory actions of 5-MeO-DMT and revealed modulatory effects on proteins associated with long-term potentiation, the formation of dendritic spines, including those involved in cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization. Our data offer the first insight about molecular alterations caused by 5-MeO-DMT in human cerebral organoids.
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Modeling medulloblastoma in vivo and with human cerebellar organoids.
Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies.
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[The potential of neural microphysiological systems (MPS)].
In vitro compound evaluation using human-derived neural cells is beginning to incorporate microphysiological systems (MPS). Neural MPS includes not only microfluidic devices but has also recently recognized neural organoids as viable MPS platforms. The history of neural MPS utilizing microfluidic devices is extensive, with the development of models that control the positioning of cell bodies and neurite outgrowth, as well as models that mimic neuronal projections through the connection of heterogeneous cell types. This paper presents examples of predicting peripheral neuropathy through machine learning applied to images of cell bodies and neurites in microfluidic devices, as well as the construction of a motor neuron-skeletal muscle model. Additionally, it discusses the responses to contraindicated drugs in Dravet syndrome using brain organoids that reflect biological brain structures. In drug discovery applications of neural MPS, it is essential to develop and utilize appropriate MPS tailored to specific objectives, ensuring biological relevance and reliability for future advancements.
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The separation of synaptic vesicles from nerve-ending particles ('synaptosomes').