Your browser does not allow saving data (e.g. private mode): bookmarks will be lost when the tab closes.
Search PubMed
Keywords, author, journal, years — results from PubMed, abstracts with Russian translation, bookmarks in your browser.
Found: 5 449
Page 56 of 545-
iPSC-induced multilineage liver organoids, small intestinal organoids and brain organoids sustain pangenotype hepatitis E virus propagation.
BACKGROUND: Hepatitis E virus (HEV), the leading global cause of acute viral hepatitis, lacks robust in vitro models for virology and pathogenesis research. OBJECTIVE: We evaluated induced pluripotent stem cell (iPSC)-induced human liver, intestinal and brain organoids (hLOs, hIOs and hBOs) as platforms for HEV infection and replication. METHODS: Multilineage organoids were infected with clinical HEV genotypes 1, 3 and 4. Viral tropism, host responses and antiviral efficacy were assessed. RESULTS: All organoids supported the complete life cycle of HEV. hLOs exhibited infection in hepatocytes, cholangiocytes, macrophages and stellate cells, accompanied by elevated interleukin-6 levels, impaired hepatic function (reduced secretion of albumin and Factor IX) and increased levels of alanine aminotransferase and aspartate aminotransferase, indicating hepatocellular injury. hIOs demonstrated broad epithelial (enterocyte, goblet, Paneth and endocrine) and mesenchymal infection, with disrupted barrier function (loss of tight junction proteins), proinflammatory cytokines upregulation and initiation of epithelial-mesenchymal transition. hBOs showed neuronal tropism, infecting glutamatergic, dopaminergic and GABAergic neurons, as well as astrocytes and oligodendrocytes. An increased number of TH+ dopaminergic neurons was observed. Ribavirin treatment in all three models partially reversed this phenotype. CONCLUSION: This study established iPSC-induced multilineage organoid infection models, confirming HEV's capacity for pan-tissue infection and revealing potential pathogenic mechanisms in the liver, intestine and nervous system. This platform provides valuable tools for HEV virology research and antiviral drug development, underscoring the unique value of organoid technology in infectious disease research.
-
Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation.
Human cerebral organoids resemble the 3D complexity of the human brain and have the potential to augment current drug development pipelines for neurological disease. Epilepsy is a complex neurological condition characterized by recurrent seizures. A third of people with epilepsy do not respond to currently available pharmaceutical drugs, and there is not one drug that treats all subtypes; thus, better models of epilepsy are needed for drug development. Cerebral organoids may be used to address this unmet need. In the present work, human cerebral organoids are used along with electrophysiological methods to explore oxygen-glucose deprivation as a hyperexcitability agent. This activity is investigated in its response to current antiseizure drugs. Furthermore, the mechanism of action of the drug candidates is probed with qPCR and immunofluorescence. The findings demonstrate OGD-induced hyperexcitable changes in the cerebral organoid tissue, which is treated with cannabidiol and bumetanide. There is evidence for NKCC1 and KCC2 gene expression, as well as other genes and proteins involved in the complex development of GABAergic signaling. This study supports the use of organoids as a platform for modelling cerebral cortical hyperexcitability that could be extended to modelling epilepsy and used for drug discovery.
-
Emerging Brain-Pathophysiology-Mimetic Platforms for Studying Neurodegenerative Diseases: Brain Organoids and Brains-on-a-Chip.
Neurodegenerative diseases are a group of disorders characterized by progressive degeneration of the structural and functional integrity of the central and peripheral nervous systems. Millions of people suffer from degenerative brain diseases worldwide, and the mortality continues to increase every year, causing a growing demand for knowledge of the underlying mechanisms and development of therapeutic targets. Conventional 2D-based cell culture platforms and animal models cannot fully recapitulate the pathophysiology, and this has limited the capability for estimating drug efficacy. Recently, engineered platforms, including brain organoids and brain-on-a-chip, have emerged. They mimic the physiology of brain tissue and reflect the fundamental pathophysiological signatures of neurodegenerative diseases, such as the accumulation of neurotoxic proteins, structural abnormalities, and functional loss. In this paper, recent advances in brain-mimetic platforms and their potential for modeling features of neurodegenerative diseases in vitro are reviewed. The development of a physiologically relevant model should help overcome unresolved neurodegenerative diseases.
-
Human cerebral organoids: the ethical stance of scientists.
BACKGROUND: Human cerebral organoids (HCOs) offer unprecedented opportunities to study the human brain in vitro, but they also raise important ethical concerns. Here we report the first systematic analysis of scientists' stance within the ethical debate. METHOD: Twenty-one in-depth semi-structured interviews were analyzed through a constant comparative method to highlight how the ethical concerns filter in the laboratory. RESULTS: The results suggest that the potential emergence of consciousness is not yet seen with concern. However, there are some features of HCO research that need to be better accounted for. Communication to the public, the use of terms such as "mini-brains", and informed consent appear to be the most pressing concerns of the scientific community. Nonetheless, respondents generally showed a positive attitude toward the ethical discussion, recognizing its value and the necessity of constant ethical scrutiny over scientific advancements. CONCLUSIONS: This research paves the way for a better-informed dialogue between scientists and ethicists, highlighting the issues to be addressed whenever scholars of different backgrounds and interests meet.
-
Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration.
Inhibitory GABAergic interneurons migrate over long distances from their extracortical origin into the developing cortex. In humans, this process is uniquely slow and prolonged, and it is unclear whether guidance cues unique to humans govern the various phases of this complex developmental process. Here, we use fused cerebral organoids to identify key roles of neurotransmitter signaling pathways in guiding the migratory behavior of human cortical interneurons. We use scRNAseq to reveal expression of GABA, glutamate, glycine, and serotonin receptors along distinct maturation trajectories across interneuron migration. We develop an image analysis software package, TrackPal, to simultaneously assess 48 parameters for entire migration tracks of individual cells. By chemical screening, we show that different modes of interneuron migration depend on distinct neurotransmitter signaling pathways, linking transcriptional maturation of interneurons with their migratory behavior. Altogether, our study provides a comprehensive quantitative analysis of human interneuron migration and its functional modulation by neurotransmitter signaling.
-
Dissecting the non-neuronal cell contribution to Parkinson's disease pathogenesis using induced pluripotent stem cells.
Parkinson's disease (PD) is an incurable age-linked neurodegenerative disease with characteristic movement impairments that are caused by the progressive loss of dopamine-containing neurons (DAn) within the substantia nigra pars compacta. It has been suggested that misfolded protein aggregates together with neuroinflammation and glial reactivity, may impact nerve cell function, leading to neurodegeneration and diseases, such as PD. However, not many studies have been able to examine the role of human glial cells in the pathogenesis of PD. With the advent of induced pluripotent stem cell (iPSC) technology, it is now possible to reprogram human somatic cells to pluripotency and to generate viable human patient-specific DA neurons and glial cells, providing a tremendous opportunity for dissecting cellular and molecular pathological mechanisms occurring at early stages of PD. This reviews will report on recent work using human iPSC and 3D brain organoid models showing that iPSC technology can be used to recapitulate PD-relevant disease-associated phenotypes, including protein aggregation, cell death or loss of neurite complexity and deficient autophagic vacuoles clearance and focus on the recent co-culture systems that are revealing new insights into the complex interactions that occur between different brain cell types during neurodegeneration. Consequently, such advances are the key to improve our understanding of PD pathology and generate potential targets for new therapies aimed at curing PD patients.
-
Engineering neural organoids: technological advances and translational frontiers.
Neural organoids have transformed experimental neuroscience by enabling human-specific models of brain development, function, and disease. Emerging at the intersection of stem cell biology and tissue engineering, these self-organizing systems recapitulate key aspects of neurogenesis, gliogenesis, and circuit formation within a controllable in vitro context. Advances in guided patterning, vascularization, and electrophysiological monitoring have enhanced structural and functional fidelity, enabling the study of dynamic processes previously inaccessible in human models. Beyond developmental biology, neural organoids have broad translational applications, including modeling neurodevelopmental and neurodegenerative disorders, screening pharmacological compounds, and testing regenerative strategies. Integration with microfluidics, bioelectronic interfaces, and computational modeling further expands their analytical capacity, transforming organoids into modular and quantifiable platforms for mechanistic and therapeutic discovery. Despite this progress, key challenges remain, including limited maturation, inter-organoid variability, and incomplete physiological integration. Addressing these limitations requires standardized differentiation protocols, robust functional benchmarks, and cross-disciplinary collaboration. The goal is not to replicate the brain in miniature, but to reconstruct its organizing principles in an experimentally accessible system. From this perspective, neural organoids serve as a bridge between biology and technology, offering new insights into human neural complexity while advancing neuroscience and medicine.
-
Electron cryo-tomography reveals the subcellular architecture of growing axons in human brain organoids.
During brain development, axons must extend over great distances in a relatively short amount of time. How the subcellular architecture of the growing axon sustains the requirements for such rapid build-up of cellular constituents has remained elusive. Human axons have been particularly poorly accessible to imaging at high resolution in a near-native context. Here, we present a method that combines cryo-correlative light microscopy and electron tomography with human cerebral organoid technology to visualize growing axon tracts. Our data reveal a wealth of structural details on the arrangement of macromolecules, cytoskeletal components, and organelles in elongating axon shafts. In particular, the intricate shape of the endoplasmic reticulum is consistent with its role in fulfilling the high demand for lipid biosynthesis to support growth. Furthermore, the scarcity of ribosomes within the growing shaft suggests limited translational competence during expansion of this compartment. These findings establish our approach as a powerful resource for investigating the ultrastructure of defined neuronal compartments.
-
Multi-walled carbon nanotubes decrease neuronal NO synthase in 3D brain organoids.
Multi-walled carbon nanotubes (MWCNTs) might induce the dysfunction of neuronal NO synthase (nNOS) and impair the function of brains. But to the best of our knowledge, this conclusion was made by using laboratory animals or conventional nerve cell cultures; however, these models might not reflect the complex conditions of human brains. Recently, the development of 3D brain organoids (also known as organotypic cultures) derived from human induced pluripotent stem cells (iPSCs) provides a platform to investigate the behaviors of human brains in vitro. In this study, we investigated the toxicity of MWCNTs to 3D brain organoids which expressed the cortical layer markers. It was shown that MWCNTs induced cytotoxicity to 3D brain organoids but not in dose-dependent manner. Exposure to high level of MWCNTs (64 μg/mL) reduced the levels of intracellular NO but increased superoxide. As the mechanism, 64 μg/mL MWCNTs significantly reduced the protein level of nNOS. The nNOS regulators nuclear factor kappa-B (NF-κB) proteins were significantly induced by MWCNTs, whereas Kruppel-like factor 4 (KLF4) proteins were reduced particularly after exposure to low level of MWCNTs (16 μg/mL). The results from fluorescence micro-optical sectioning tomography (MOST) confirmed the decrease of nNOS proteins, not only at the out-layers that directly contacted MWCNTs, but also at the inner-layers. Combined, our results suggested that MWCNTs could decrease nNOS activity by inducing oxidative stress and modulating NF-κB-KLF4 pathway. This study also showed the potential of 3D brain organoids in mechanism-based toxicology studies.
-
One-Stop Microfluidic Assembly of Human Brain Organoids To Model Prenatal Cannabis Exposure.
Prenatal cannabis exposure (PCE) influences human brain development, but it is challenging to model PCE using animals and current cell culture techniques. Here, we developed a one-stop microfluidic platform to assemble and culture human cerebral organoids from human embryonic stem cells (hESC) to investigate the effect of PCE on early human brain development. By incorporating perfusable culture chambers, air-liquid interface, and one-stop protocol, this microfluidic platform can simplify the fabrication procedure and produce a large number of organoids (169 organoids per 3.5 cm × 3.5 cm device area) without fusion, as compared with conventional fabrication methods. These one-stop microfluidic assembled cerebral organoids not only recapitulate early human brain structure, biology, and electrophysiology but also have minimal size variation and hypoxia. Under on-chip exposure to the psychoactive cannabinoid, Δ-9-tetrahydrocannabinol (THC), cerebral organoids exhibited reduced neuronal maturation, downregulation of cannabinoid receptor type 1 (CB1) receptors, and impaired neurite outgrowth. Moreover, transient on-chip THC treatment also decreased spontaneous firing in these organoids. This one-stop microfluidic technique enables a simple, scalable, and repeatable organoid culture method that can be used not only for human brain organoids but also for many other human organoids including liver, kidney, retina, and tumor organoids. This technology could be widely used in modeling brain and other organ development, developmental disorders, developmental pharmacology and toxicology, and drug screening.