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Page 135 of 547-
Accumulation of smooth cisterns, multivesicular bodies and "zebra" bodies in neurons. A case of peculiar storage condition.
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Brain-wide neuronal circuit connectome of human glioblastoma.
Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumour progression1,2. Synaptic inputs onto GBM cells identified so far are largely short range and glutamatergic3,4. The extent of GBM integration into the brain-wide neuronal circuitry remains unclear. Here we applied rabies virus-mediated and herpes simplex virus-mediated trans-monosynaptic tracing5,6 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrate into diverse local and long-range neural circuits across the brain. Beyond glutamatergic inputs, we identified various neuromodulatory inputs, including synapses between basal forebrain cholinergic neurons and GBM cells. Acute acetylcholine stimulation induces long-lasting elevation of calcium oscillations and transcriptional reprogramming of GBM cells into a more motile state via the metabotropic CHRM3 receptor. CHRM3 activation promotes GBM cell motility, whereas its downregulation suppresses GBM cell motility and prolongs mouse survival. Together, these results reveal the striking capacity for human GBM cells to rapidly and robustly integrate into anatomically diverse neuronal networks of different neurotransmitter systems. Our findings further support a model in which rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumour fitness.
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New tools offer clues to how the human brain takes shape.
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Comparing stem cells, transdifferentiation and brain organoids as tools for psychiatric research.
The inaccessibility of neurons coming directly from patients has hindered our understanding of mental illnesses at the cellular level. To overcome this obstacle, six different cellular approaches that carry the genetic vulnerability to psychiatric disorders are currently available: Olfactory Neuroepithelial Cells, Mesenchymal Stem Cells, Pluripotent Monocytes, Induced Pluripotent Stem Cells, Induced Neuronal cells and more recently Brain Organoids. Here we contrast advantages and disadvantages of each of these six cell-based methodologies. Neuronal-like cells derived from pluripotent monocytes are presented in more detail as this technique was recently used in psychiatry for the first time. Among the parameters used for comparison are; accessibility, need for reprograming, time to deliver differentiated cells, differentiation efficiency, reproducibility of results and cost. We provide a timeline on the discovery of these cell-based methodologies, but, our main goal is to assist researchers selecting which cellular approach is best suited for any given project. This manuscript also aims to help readers better interpret results from the published literature. With this goal in mind, we end our work with a discussion about the differences and similarities between cell-based techniques and postmortem research, the only currently available tools that allow the study of mental illness in neurons or neuronal-like cells coming directly from patients.
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Human striatal organoids derived from pluripotent stem cells recapitulate striatal development and compartments.
The striatum links neuronal circuits in the human brain, and its malfunction causes neuronal disorders such as Huntington's disease (HD). A human striatum model that recapitulates fetal striatal development is vital to decoding the pathogenesis of striatum-related neurological disorders and developing therapeutic strategies. Here, we developed a method to construct human striatal organoids (hStrOs) from human pluripotent stem cells (hPSCs), including hStrOs-derived assembloids. Our hStrOs partially replicated the fetal striatum and formed striosome and matrix-like compartments in vitro. Single-cell RNA sequencing revealed distinct striatal lineages in hStrOs, diverging from dorsal forebrain fate. Using hStrOs-derived assembloids, we replicated the striatal targeting projections from different brain parts. Furthermore, hStrOs can serve as hosts for striatal neuronal allografts to test allograft neuronal survival and functional integration. Our hStrOs are suitable for studying striatal development and related disorders, characterizing the neural circuitry between different brain regions, and testing therapeutic strategies.
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Morphology, organelles and susceptibility to viruses of cultured ferret cells.
Cells explanted from a normal 6-week-old ferret's brain have been subcultured over 100 times, have undergone over 400 population doublings, possess ferret-specific antigens and are referred to as Mpf cells. Low passage-level Mpf cells formed diffuse colonies with ill-defined borders which had a swirling 'finger-print' pattern whereas the colonies formed by high passage-level cells were more densely populated and had distinct borders. Mpf cells at their 100th passage level appeared as a loose monolayer with ill-defined cytoplasmic borders and contained microfilaments, ovoid nuclei, granular endoplasmic reticula with large dilated cisternae filled with an amorphous medium electron-dense product, abundant free ribosomes, irregular and hypertrophic Golgi bodies, mitochondria, and lipid inclusions associated with lipofuscin deposits. Chains of vesicles, 120-150 nm in diameter, some opening to the exterior, were aligned at the cytoplasmic border. The Mpf cells exhibited cytopathology and synthesized progeny virus when exposed to representatives of the Arboviruses, Arenoviruses, Paramyxoviruses, Poxviruses, Retroviruses and Rhabdoviruses.
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Modeling amyloid beta and tau pathology in human cerebral organoids.
The typical abnormalities observed in the brain of Alzheimer's disease (AD) patients include synaptic alterations, neuronal death, brain inflammation, and the accumulation of protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Despite the development of many animal and in vitro models for AD, there is a lack of an experimental approach that fully recapitulates essential aspects of the disease in human cells. Here, we report the generation of a new model to study AD, consisting of cerebral organoids (COs) produced from human-induced pluripotent stem cells (iPSCs). Under our experimental conditions, COs grow to form three-dimensional (3D) structures containing neural areas with cortical-like organization. Analysis of COs by histological and biochemical methods revealed that organoids produced from iPSCs derived from patients affected by familial AD or Down syndrome (DS) spontaneously develop over time pathological features of AD, including accumulation of structures highly reminiscent to amyloid plaques and neurofibrillary tangles. These pathological abnormalities were not observed in COs generated from various controls, including human iPSCs from healthy individuals, human iPSCs from patients affected by Creutzfeldt-Jakob disease, mouse embryonic stem cells (ESCs), or mouse iPSCs. These findings enable modeling genetic AD in a human cellular context in a 3D cortical-like tissue developed in vitro from patient-specific stem cells. This system provides a more relevant disease model compared to pre-existing methods and offers a new platform for discovery of novel targets and screening of drugs for therapeutic intervention.
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The One-Stop Gyrification Station - Challenges and New Technologies.
The evolution of the folded cortical surface is an iconic feature of the human brain shared by a subset of mammals and considered pivotal for the emergence of higher-order cognitive functions. While our understanding of the neurodevelopmental processes involved in corticogenesis has greatly advanced over the past 70 years of brain research, the fundamental mechanisms that result in gyrification, along with its originating cytoarchitectural location, remain largely unknown. This review brings together numerous approaches to this basic neurodevelopmental problem, constructing a narrative of how various models, techniques and tools have been applied to the study of gyrification thus far. After a brief discussion of core concepts and challenges within the field, we provide an analysis of the significant discoveries derived from the parallel use of model organisms such as the mouse, ferret, sheep and non-human primates, particularly with regard to how they have shaped our understanding of cortical folding. We then focus on the latest developments in the field and the complementary application of newly emerging technologies, such as cerebral organoids, advanced neuroimaging techniques, and atomic force microscopy. Particular emphasis is placed upon the use of novel computational and physical models in regard to the interplay of biological and physical forces in cortical folding.
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Characterization of enhancer activity in early human neurodevelopment using Massively Parallel Reporter Assay (MPRA) and forebrain organoids.
Regulation of gene expression through enhancers is one of the major processes shaping the structure and function of the human brain during development. High-throughput assays have predicted thousands of enhancers involved in neurodevelopment, and confirming their activity through orthogonal functional assays is crucial. Here, we utilized Massively Parallel Reporter Assays (MPRAs) in stem cells and forebrain organoids to evaluate the activity of ~ 7000 gene-linked enhancers previously identified in human fetal tissues and brain organoids. We used a Gaussian mixture model to evaluate the contribution of background noise in the measured activity signal to confirm the activity of ~ 35% of the tested enhancers, with most showing temporal-specific activity, suggesting their evolving role in neurodevelopment. The temporal specificity was further supported by the correlation of activity with gene expression. Our findings provide a valuable gene regulatory resource to the scientific community.
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Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells.
Cortico-striatal projections are critical components of forebrain circuitry that regulate motivated behaviors. To enable the study of the human cortico-striatal pathway and how its dysfunction leads to neuropsychiatric disease, we developed a method to convert human pluripotent stem cells into region-specific brain organoids that resemble the developing human striatum and include electrically active medium spiny neurons. We then assembled these organoids with cerebral cortical organoids in three-dimensional cultures to form cortico-striatal assembloids. Using viral tracing and functional assays in intact or sliced assembloids, we show that cortical neurons send axonal projections into striatal organoids and form synaptic connections. Medium spiny neurons mature electrophysiologically following assembly and display calcium activity after optogenetic stimulation of cortical neurons. Moreover, we derive cortico-striatal assembloids from patients with a neurodevelopmental disorder caused by a deletion on chromosome 22q13.3 and capture disease-associated defects in calcium activity, showing that this approach will allow investigation of the development and functional assembly of cortico-striatal connectivity using patient-derived cells.