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Intraepithelial inclusions resembling human biondi bodies in the choroid plexus of an aged chimpanzee.
Complex intracellular inclusion bodies of the Biondi type were observed in the choroidal epithelium (choroid plexus of the lateral ventricle) of a 43-year-old male chimpanzee. The specific components of these inclusions are bundles of filaments 8-15 nm in diameter, which are associated with lipid droplets and a wide variety of unidentified inclusions of differing electron density. Biondi bodies are characteristic inclusions of the choroid plexus of aged humans but have been claimed to be absent from the choroidal epithelium of senescent animals including nonhuman primates. The present finding of Biondi body-like inclusions in an aged chimpanzee underscores the usefulness of nonhuman primates as models for studies of aging, seeking to gain a better understanding of gerontological aspects of the human brain.
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Cytological observations on the ventromedial hypothalamic nucleus.
Two sorts of neurons are recognized in Golgi impregnations of the rat ventromedial hypothalamic nucleus (HVM). The two cell types, category I and II neurons, are differentiated on the basis of their somatic, dendritic, and axonal characteristics. Category I neurons form most of the neuronal population and are located throughout HVM. The small number of category II neurons that have been studied occur in lateral HVM. Two varieties of neuronal profile, "common" and "uncommon cells", are seen in thin sections of HVM. The "uncommon cells", in comparison with the "common ones", appear to have a larger soma, a more electron-dense cytoplasmic matrix, an abundance of Nissl bodies, and a population of dense-cored vesicles (100--130 nm in diameter). Some of the somata and proximal dendrites of "common", but not "uncommon" cells, are wrapped in multiple layers of astrocytic processes. Although the correlation is tentative, it is argued that category I neurons correspond to "common cells" and category II, to "uncommon cells". One possible implication of this correspondence is discussed regarding neuronal alteration in response to change in the endocrinological environment of the brain.
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The distribution, relationships to other organelles, and calcium-sequestering ability of smooth endoplasmic reticulum in frog olfactory axons.
Ultrastructural studies of single and serial sections of bullfrog olfactory axons showed that smooth endoplasmic reticulum (SER) tubules, which usually appear as single profiles in cross-sections of axons, are continuous over considerable distances, but that discontinuities do exist. Computer-assisted three-dimensional reconstruction of portions of axons indicated that the SER tubules show considerable variation in the volume of the cisternal space along the tubule, which often follows a tortuous path. Some branching and anastomosing appears to occur, and electron-dense material was present in the cisternal space of some tubules. SER tubules are often bridged to neurofilaments and less often to microtubules. The usual two to three microtubules in the axoplasm form a domain which is characterized by a clear area, or zone of exclusion, around the microtubules. Ultrastructural cytochemistry was used to demonstrate that SER tubules actively sequester Ca. The electron-dense product (calcium oxalate) was uniformly and specifically associated with the SER of axons at both proximal (closest to the perikarya in the olfactory epithelium) and distal (closest to the olfactory lobe of the brain) ends of the olfactory nerve. It is concluded that the primary function of SER tubules in these axons is to serve in the regulation of Ca in the axoplasm, probably to facilitate fast axoplasmic transport, and that a secondary function may be the translocation of material in the cisternal space. The observations are discussed as they may relate to the "microstream" hypothesis of axoplasmic transport, and it is argued that fast transport occurs through the zone of exclusion associated with the microtubule domain(s) of axons.
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Spatiotemporal expression of thyroid hormone transporter MCT8 and THRA mRNA in human cerebral organoids recapitulating first trimester cortex development.
Thyroid hormones (TH) play critical roles during nervous system development and patients carrying coding variants of MCT8 (monocarboxylate transporter 8) or THRA (thyroid hormone receptor alpha) present a spectrum of neurological phenotypes resulting from perturbed local TH action during early brain development. Recently, human cerebral organoids (hCOs) emerged as powerful in vitro tools for disease modelling recapitulating key aspects of early human cortex development. To begin exploring prospects of this model for thyroid research, we performed a detailed characterization of the spatiotemporal expression of MCT8 and THRA in developing hCOs. Immunostaining showed MCT8 membrane expression in neuronal progenitor cell types including early neuroepithelial cells, radial glia cells (RGCs), intermediate progenitors and outer RGCs. In addition, we detected robust MCT8 protein expression in deep layer and upper layer neurons. Spatiotemporal SLC16A2 mRNA expression, detected by fluorescent in situ hybridization (FISH), was highly concordant with MCT8 protein expression across cortical cell layers. FISH detected THRA mRNA expression already in neuroepithelium before the onset of neurogenesis. THRA mRNA expression remained low in the ventricular zone, increased in the subventricular zone whereas strong THRA expression was observed in excitatory neurons. In combination with a robust up-regulation of known T3 response genes following T3 treatment, these observations show that hCOs provide a promising and experimentally tractable model to probe local TH action during human cortical neurogenesis and eventually to model the consequences of impaired TH function for early cortex development.
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How mechanisms of stem cell polarity shape the human cerebral cortex.
Apical-basal progenitor cell polarity establishes key features of the radial and laminar architecture of the developing human cortex. The unique diversity of cortical stem cell populations and an expansion of progenitor population size in the human cortex have been mirrored by an increase in the complexity of cellular processes that regulate stem cell morphology and behaviour, including their polarity. The study of human cells in primary tissue samples and human stem cell-derived model systems (such as cortical organoids) has provided insight into these processes, revealing that protein complexes regulate progenitor polarity by controlling cell membrane adherence within appropriate cortical niches and are themselves regulated by cytoskeletal proteins, signalling molecules and receptors, and cellular organelles. Studies exploring how cortical stem cell polarity is established and maintained are key for understanding the features of human brain development and have implications for neurological dysfunction.
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Reduced proliferation and excess astrogenesis of Pax6 heterozygous neural stem/progenitor cells.
Neural stem/progenitor cells (NSPCs) are generated in early embryonic brains and maintained to produce neurons and glial cells in the central nervous system throughout the lifespan. A transcription factor Pax6 is a pivotal player in various neurodevelopmental processes. Previously, we have shown that Pax6 heterozygous rodents have defects in hippocampal neurogenesis and production of olfactory bulb interneurons. However, characters of NSPCs derived from Pax6 heterozygous rodents have not been studied in vitro. Here we examined the maintenance/proliferation and differentiation of Pax6 heterozygous mutant (rSey(2)/+) rat NSPCs in the neurosphere culture system. We found that the proliferative activity of NSPCs derived from rSey(2)/+ rats was reduced after serial passages. We also observed an excess astrogenesis in serially passaged NSPCs from rSey(2)/+ rats. These results show that Pax6 is essential for maintaining NSPCs and determining their differentiation fates.
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Transcript errors generate amyloid-like proteins in huwman cells.
Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.
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Modeling medulloblastoma pathogenesis and treatment in human cerebellar organoids.
Medulloblastoma (MB) groups 3 and 4 arise from human-specific developmental contexts that remain experimentally inaccessible, limiting mechanistic insight into tumor initiation. We generated cerebellar organoids (CbOs) from expanded potential stem cells (EPSCs) and performed integrated single-cell transcriptomic and DNA methylation analyses, revealing discrete human rhombic lip progenitor populations whose developmental programs align with group 3- and group 4-associated lineages. Using c-MYC overexpression as an initiating oncogenic event, we demonstrated that these lineage-restricted progenitors are susceptible to neoplastic transformation, generating tumors with group 3 MB molecular features in vitro and in vivo. We further established a CbO-MB coculture system that preserves malignant and nonmalignant cellular compartments, hence enabling interrogation of tumor-microenvironment interactions and providing simultaneous readouts of antitumor efficacy and cerebellar toxicity upon drug treatment. Receptor-ligand modeling in this system identifies TGFβ paracrine signaling as a microenvironmental pathway supporting MB growth, which we validated pharmacologically. Further analyses of cocultured MB cells revealed a myogenic differentiation program enriched in MYC-driven MB and recurrent disease, which is associated with poorer prognosis. Together, this work establishes a collection of CbO models for studying group 3/4 MB initiation, growth, and microenvironmental dependencies and provides a tractable platform for further mechanistic and therapeutic investigation of these tumors.
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Advances in microfluidic in vitro systems for neurological disease modeling.
Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to "Organ-on-chip" models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and "Organ-on-chip" systems have enabled new understanding of metabolic coupling and blood-brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from "Organ-on-chip" to "Disease-on-chip." This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases.
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Brain-on-a-Chip: A Human 3D Model for Clinical Application.
The main goal of this research is to design, develop and implement an efficient protocol to generate 3D neural cultures derived from human induced Pluripotent Stem Cells (hiPSCs) coupled to Micro Electrode Arrays (MEA) in order to obtain an engineered and controlled brain-on-a-chip model. The use of patient specific iPSCs may offer novel insights into the pathophysiology of a large variety of disorders, including numerous neurodevelopmental and late-onset neurodegenerative conditions. With these in vitro patient specific models, we may have the possibility to test drugs and find ad hoc therapies in the direction of precision medicine.