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Glial cell diversity and methamphetamine-induced neuroinflammation in human cerebral organoids.
Methamphetamine (METH) is a potent stimulant that induces a euphoric state but also causes cognitive impairment, neurotoxicity and neurodevelopmental deficits. Yet, the molecular mechanisms by which METH causes neurodevelopmental defects have remained elusive. Here we utilized human cerebral organoids and single-cell RNA sequencing (scRNA-seq) to study the effects of prenatal METH exposure on fetal brain development. We analyzed 20,758 cells from eight untreated and six METH-treated cerebral organoids and found that the organoids developed from embryonic stem cells contained a diverse array of glial and neuronal cell types. We further identified transcriptionally distinct populations of astrocytes and oligodendrocytes within cerebral organoids. Treatment of organoids with METH-induced marked changes in transcription in multiple cell types, including astrocytes and neural progenitor cells. METH also elicited novel astrocyte-specific gene expression networks regulating responses to cytokines, and inflammasome. Moreover, upregulation of immediate early genes, complement factors, apoptosis, and immune response genes suggests a neuroinflammatory program induced by METH regulating neural stem cell proliferation, differentiation, and cell death. Finally, we observed marked METH-induced changes in neuroinflammatory and cytokine gene expression at the RNA and protein levels. Our data suggest that human cerebral organoids represent a model system to study drug-induced neuroinflammation at single-cell resolution.
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Ultrastructural study of two central nervous system lymphomas.
Electron microscopy was performed on two CNS lymphomas, one primary and the second a skull metastasis from a brain primary lymphoma. The former revealed a tumor perivascularly arranged, which was composed of rounded cells having no specialized organellae. Biopsies from the primary and metastasis of the second case revealed a predominance of rounded cells with scanty cytoplasm, another population of cells with phagocytic activity and a third group with elongated ctyoplasmic processes which stain positively for microglia. By electron microscopy some of these processes resembled neurites or oligondendroglia, while others suggested an astrocytic appearance.
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In vitro assays as a tool to personalize treatment in central nervous system tumors: a systematic literature review.
Personalized therapy in neuro-oncology has traditionally relied on molecular profiling. However, clinical benefit has been scarce to date. Recently, in vitro drug sensitivity testing using patient-derived models-such as organoids and cell lines-has emerged as a promising strategy. We systematically reviewed evidence on the efficacy of in vitro drug screening in predicting treatment outcome for brain tumors, including but not limited to glioblastoma. PRISMA guidelines were followed. Fifteen studies were included, comprising 300 patients overall. Cohort studies built the largest group; only one randomized clinical trial was found. In vitro assays, using patient-derived stem cells, standardized assays ad the ChemoID, or tumor-derived organoids, were able to reliably predict treatment outcome. However, the overall quality of evidence was limited. These models may overcome limitations of molecular profiling, especially in glioblastoma, where driver mutations are often lacking and the molecular profile evolves at recurrence. Although initial results are promising, further validation is needed before clinical implementation.
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A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
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SARS-CoV-2 research using human pluripotent stem cells and organoids.
Experimental cell models are indispensable for clarifying the pathophysiology of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and for developing therapeutic agents. To recapitulate the symptoms and drug response of COVID-19 patients in vitro, SARS-CoV-2 studies using physiologically relevant human embryonic stem (ES)/induced pluripotent stem (iPS) cell-derived somatic cells and organoids are ongoing. These cells and organoids have been used to show that SARS-CoV-2 can infect and damage various organs including the lung, heart, brain, intestinal tract, kidney, and pancreas. They are also being used to develop COVID-19 therapeutic agents, including evaluation of their antiviral efficacy and safety. The relationship between COVID-19 aggravation and human genetic backgrounds has been investigated using genetically modified ES/iPS cells and patient-derived iPS cells. This review summarizes the latest results and issues of SARS-CoV-2 research using human ES/iPS cell-derived somatic cells and organoids.
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Visualization of centrioles and basal bodies by fluorescent staining with nonimmune rabbit sera.
Several sera from nonimmunized rabbits have been found which stain centrioles and basal bodies by indirect immunofluorescence in a wide variety of cell types. So far, approximately 10% of the rabbit sera that we have examined gave strong positive staining of centrioles and basal bodies. Cytoplasmic networks, mitotic spindles, and ciliary axonemes, however, remain unstained. This specific fluorescent staining of centrioles and basal bodies could not be abolished by absorption of sera with purified brain tubulin. This technique is superior to previous methods for the visualization of basal bodies and centrioles at the light microscopic level and should be useful for rapid and convenient detection of these organelles in large populations of cells.
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Disrupted inhibitory interneuron development in SCN1A Dravet syndrome revealed by patient-derived subpallial organoids.
OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by loss-of-function variants in SCN1A, with seizures typically emerging during the first year of life. Although DS pathophysiology has largely been attributed to inhibitory network dysfunction underlying seizures, early developmental alterations in inhibitory interneurons remain poorly understood. METHODS: We generated inhibitory interneuron-enriched subpallial organoids from patient-derived induced pluripotent stem cells carrying an SCN1A loss-of-function variant and the corresponding isogenic control. Using complementary molecular and functional approaches, including quantitative polymerase chain reaction, bulk RNA sequencing, whole-cell patch-clamp electrophysiology, and two-photon calcium imaging, we investigated early inhibitory interneuron development and functional maturation in a human cellular context. RESULTS: Transcriptomic profiling revealed early dysregulation of ventral forebrain interneuron developmental programs, including altered expression of medial ganglionic eminence-associated transcriptional regulators, preceding inhibitory network dysfunction. Patient-derived organoids exhibited marked reductions in intrinsic neuronal excitability and synaptic activity. Acute application of fenfluramine, a clinically approved antiseizure medication for DS, partially restored neuronal activity, demonstrating the translational relevance of this model. SIGNIFICANCE: These findings demonstrate that SCN1A loss of function disrupts early inhibitory interneuron development and functional maturation, defining a developmental vulnerability that likely precedes the emergence of epilepsy in DS. This work establishes patient-derived inhibitory organoids as a human-relevant platform for dissecting disease mechanisms and evaluating therapeutic responses in SCN1A-related epileptic encephalopathies.
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Single-cell RNA sequencing analysis of SARS-CoV-2 entry receptors in human organoids.
Coronavirus disease-2019 (COVID-19) is a global pandemic and caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has resulted in millions of deaths worldwide. Reports denote SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) as its primary entry point into the host cell. However, understanding the biology behind this viral replication, disease mechanism and drug discovery efforts are limited due to the lack of a suitable experimental model. Here, we used single-cell RNA sequencing data of human organoids to analyze expressions of ACE2 and TMPRSS2, in addition to an array of RNA receptors to examine their role in SARS-CoV-2 pathogenesis. ACE2 is abundant in all organoids, except the prostate and brain, and TMPRSS2 is omnipresent. Innate immune pathways are upregulated in ACE2(+) cells of all organoids, except the lungs. Besides this, the expression of low-density lipoprotein receptor is highly enriched in ACE2(+) cells in intestinal, lung, and retinal organoids, with the highest expression in lung organoids. Collectively, this study demonstrates that the organoids can be used as an experimental platform to explore this novel virus disease mechanism and for drug development.
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Meningeal melanocytoma ("melanotic meningioma"). Its melanocytic origin as revealed by electron microscopy.
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Primary cerebral reticulosis and plasma cell diffenentiation.
Cerebral proliferative and tumour forming reticulosis are primary pathologic processes of the brain originating in the perivascular adventitial cell. In these conditions this cell can transform into a histiocyte or microglial cell with characters of a macrophage. A reactive cell with endoplasmic reticulum, basement membrane and fibril forming properties, is also present (fibril forming reticular cell). The malignant tumours of the perivascular spaces (cerebral reticulosarcoma) are characterized by the presence of the dedifferentiated cells originating from the intraadventitial cell. Under both proliferative and tumour forming conditions this cell may transform into a cell rich in endoplasmic reticulum, sometimes charged with Russell bodies and corresponds morphologically to the protein-forming plasma cell. The properties of the intracerebral periadventitial cells are identical with those of the reticulo-histiocytic system described by ASCHOFF. As its structure and the elements into which it differentiats sharply differ from those of the cells belonging to the lymphocyte series the term malignant lymphoma of the brain given to these processes does not correspond to the fundamental characters of these pathological process.