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: 5 473
Page 213 of 548-
Modeling PTEN overexpression-induced microcephaly in human brain organoids.
The phosphatase and tensin homolog (PTEN) protein, encoded by the PTEN gene on chromosome 10, is a negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. Loss of PTEN has been linked to an array of human diseases, including neurodevelopmental disorders such as macrocephaly and autism. However, it remains unknown whether increased dosage of PTEN can lead to human disease. A recent human genetics study identifies chromosome 10 microduplication encompassing PTEN in patients with microcephaly. Here we generated a human brain organoid model of increased PTEN dosage. We showed that mild PTEN overexpression led to reduced neural precursor proliferation, premature neuronal differentiation, and the formation of significantly smaller brain organoids. PTEN overexpression resulted in decreased AKT activation, and treatment of wild-type organoids with an AKT inhibitor recapitulated the reduced brain organoid growth phenotypes. Together, our findings provide functional evidence that PTEN is a dosage-sensitive gene that regulates human neurodevelopment, and that increased PTEN dosage in brain organoids results in microcephaly-like phenotypes.
-
Magnetoelectric core-shell nanoparticles for nervous tissue electrostimulation: Performance in In vitro and ex vivo organotypic cultures.
This work presents functional multiferroic cobalt ferrite-based nanoparticles (CFO NPs) coated with calcium/zirconium-doped barium titanate (CFO-BCZT) that demonstrate notable magnetoelectric coupling and biocompatibility for neural applications. The core-shell structure was synthesized through hydrothermal and sol-gel processes. Uncoated CFO NPs and CFO NPs coated with bismuth ferrite (CFO-BFO) were used for comparison. X-ray diffraction revealed cubic CFO core and tetragonal BCZT shell without any secondary phase, nor impurities. Magnetoelectric coupling effect of CFO-BCZT MENPs was revealed through piezoresponse force microscopy. Biological cellular responses to CFO-BCZT MENPs were evaluated through cytotoxicity assays, microscopy analysis, and cellular uptake on primary neurons, astrocytes or microglia cultures. Long-term effects were studied in rodent 3D organotypic hippocampal cultures. Moreover, the magnetoelectric performance of CFO-BCZT and CFO-BFO MENPs was assessed in vitro with SH-SY5Y human neuronal cell lines under magnetic stimulation. The results showed CFO-BCZT MENPs superior biocompatibility both in vitro and ex vivo in organotypic brain slices, while CFO-BFO MENPs reduced microglial viability and induced inflammatory changes. Additionally, tissue penetration of CFO-BCZT MENPs through magnetic attraction was successfully achieved on organotypic hippocampal cultures, without causing either cell damage or disruption of neural connections. Finally, SH-SY5Y neuronal cell line showed good neurite outgrowth with the tested magnetic stimulation parameters. In conclusion, CFO-BCZT MENPs not only exhibited a magnetoelectric coupling effect but also greater biocompatibility compared to CFO-BFO and uncoated CFO NPs, positioning them as promising composite materials for brain stimulation therapies. STATEMENT OF SIGNIFICANCE: Magnetoelectric nanoparticles are emerging as promising tools for non-invasive brain stimulation therapies. Our work introduces biocompatible multiferroic cobalt ferrite- based nanoparticles (CFO NPs) coated with calcium/zirconium-doped barium titanate (CFO-BCZT) as candidate materials for neural applications, representing a combination of cobalt ferrite cores with calcium/zirconium-doped barium titanate shells. These core-shell nanostructures exhibit strong magnetoelectric coupling and significantly improved biocompatibility compared to conventional alternatives, such as bismuth ferrite coatings. Their ability to penetrate brain tissue through magnetic attraction without inducing cellular toxicity or inflammation on ex vivo organotypic hippocampal slices, while promoting neurite outgrowth on in vitro neuronal cell cultures, positions them as promising tools for non-invasive neural modulation. This study paves the way for safe, wireless brain stimulation platforms using multifunctional nanomaterials.
-
From Organoids to Organ-on-Chip: Advancing Human-Relevant Models for Viral Pathogenesis and Antiviral Drug Discovery.
Organoid and organ-on-chip technologies are rapidly evolving platforms for viral research that integrate stem cell biology, tissue engineering, and microfluidics to recapitulate key structural, mechanical, biochemical, and cellular features of human and animal physiology. By incorporating multicellular organoids into perfused microfluidic systems, these models can provide complex, dynamic, and physiologically relevant micro-environments for investigating virus-host interactions that are difficult to capture in conventional two-dimensional cultures and static organoids. Controlled flow, shear stress, extracellular matrix organization, tissue-tissue interfaces, and multicellular signaling enable mechanistic investigation of viral infectivity, dissemination, tissue injury and immune activation. Integration of real-time imaging and biosensors further permits longitudinal monitoring of viral replication, host responses, and tissue integrity, expanding the potential of these platforms for antiviral drug discovery. Recent organoid-on-chip studies using brain, skin, vaginal, respiratory, and intestinal models have demonstrated how tissue architecture, mechanical forces, glycocalyx dynamics, and immune-stromal interactions influence viral tropism and pathogenesis. In this review, we provide a mechanistic and translational overview of organoid and organ-on-chip technologies for studying viral infections, with particular emphasis on models of herpes simplex virus (HSV)-mediated disease. We further examine advances in immune integration, multi-organ systems, biosensing, and computational approaches that are expanding the complexity and predictive potential of these models. Importantly, patient-derived organoids and organ-on-chip platforms can capture interindividual differences in viral susceptibility, host responses, and therapeutic efficacy, providing pharmaceutical research with more precise, patient-relevant data to support drug prioritization and precision antiviral medicine. Finally, we discuss key barriers to broader adoption, including organoid maturation, biological and technical variability, reproducibility, scalability, biosafety, cost, standardization, and regulatory validation. Collectively, these advances position organoid and organ-on-chip technologies as powerful human-relevant models that bridge reductionist in vitro systems and human disease, while continued optimization, standardization, and validation will be essential to realize their full potential for mechanistically informed antiviral discovery, therapeutic development, and precision medicine.
-
Rubella virus tropism and single-cell responses in human primary tissue and microglia-containing organoids.
Rubella virus is an important human pathogen that can cause neurological deficits in a developing fetus when contracted during pregnancy. Despite successful vaccination programs in the Americas and many developed countries, rubella remains endemic in many regions worldwide and outbreaks occur wherever population immunity is insufficient. Intense interest since rubella virus was first isolated in 1962 has advanced our understanding of clinical outcomes after infection disrupts key processes of fetal neurodevelopment. Yet it is still largely unknown which cell types in the developing brain are targeted. We show that in human brain slices, rubella virus predominantly infects microglia. This infection occurs in a heterogeneous population but not in a highly microglia-enriched monoculture in the absence of other cell types. By using an organoid-microglia model, we further demonstrate that rubella virus infection leads to a profound interferon response in non-microglial cells, including neurons and neural progenitor cells, and this response is attenuated by the presence of microglia.
-
Harnessing cerebral organoids for Alzheimer's disease research.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting the aging population. Despite many studies, there remains an urgent need to identify the root causes of AD, together with potential treatments. Cerebral organoid technology has made it possible to model human neurophysiology and disease with increasing accuracy in patient-derived tissue cultures. Here, we review the most recent advances in modeling AD in organoids and other engineered three-dimensional cell culture systems. Early studies demonstrated that familial AD patient-derived organoids robustly develop disease pathology. Ongoing work has expanded this focus to investigate the genetic and environmental causes of late-onset sporadic AD and harness organoids for high-throughput drug screens. Future organoid models will need to incorporate additional cell types and tissues implicated in disease pathogenesis, including microglia and vasculature. We anticipate the continuation of this rapid progress in developing cerebral organoid technology toward facilitating our understanding of and informing treatment strategies for AD.
-
Organoids as brain tumour models: bridging the translational gap.
Advances in stem cell-derived brain organoids, enabled by the generation of human reprogrammed pluripotent stem cells, have significantly expanded the repertoire of models available for brain tumour research. These approaches have predominantly been applied to glioblastoma and medulloblastoma, leveraging brain region-specific cerebral/cortical or cerebellar organoids, respectively. Organoids have the potential to close the gap between current two-dimensional cell-based brain tumour models and patients, while helping to address the limitations of animal models. In this At a Glance article, we outline current stem cell-derived organoid-based brain tumour models and how they have expanded our understanding of paediatric and adult brain tumours, including their onset, heterogeneity and treatment. We also describe how these organoids are currently being refined toward more accurate, clinically relevant models and highlight future directions to improve their translatability.
-
Mini-organs with big impact: Organoids in liver cancer studies.
Hepatocellular carcinoma, the most common primary liver cancer and a leading cause of death, is a difficult disease to treat due to its heterogeneous nature. Traditional models, such as 2D culture and patient-derived xenografts, have not proven effective. However, the development of 3D culture techniques, such as organoids, which can mimic the tumor microenvironment (TME) and preserve heterogeneity and pathophysiological properties of tumor cells, offers new opportunities for treatment and research. Organoids also have the potential for biomarker detection and personalized medication, as well as genome editing using CRISPR/Cas9 to study the behavior of certain genes and therapeutic interventions. This review explores to-the-date development of organoids with a focus on TME modeling in 3D organoid cultures. Further, it discusses gene editing using CRISPR/Cas9 in organoids, the challenges faced, and the prospects in the field of organoids.
-
Establishment and Validation of a Model for Fetal Neural Ischemia Using Necrotic Core-Free Human Spinal Cord Organoids.
Fetal spinal cord ischemia is a serious medical condition that can result in significant neurological damage and adverse outcomes for the fetus. However, the lack of an appropriate experimental model has hindered the understanding of the pathology and the development of effective treatments. In our study, we established a system for screening drugs that affect fetal spinal cord ischemia using spinal cord organoids. Importantly, we produced necrotic core-free human spinal cord organoids (nf-hSCOs) by reducing the organoid size to avoid potential complications of spontaneous necrosis in large organoids. Exposing nf-hSCOs to CoCl2 as a hypoxia mimetic and hypoglycemic conditions resulted in significant neuronal damage, as assessed by multiple assay batteries. By utilizing this model, we tested chemicals that have been reported to exhibit beneficial effects in brain organoid-based ischemia models. Surprisingly, these chemicals did not provide sufficient benefit, and we discovered that rapamycin is a mild neuroprotective reagent for both axon degeneration and neuronal survival. We propose that nf-hSCO is suitable for large-scale screening of fetal neural ischemia due to its scalability, ease of ischemic induction, implementation of quantifiable assay batteries, and the absence of spontaneous necrosis.
-
A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity.
Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.
-
Mice 3D testicular organoid system as a novel tool to study Zika virus pathogenesis.
Zika virus (ZIKV) poses a serious threat to global public health due to its close relationship with neurological and male reproductive damage. However, deficiency of human testicular samples hinders the in-depth research on ZIKV-induced male reproductive system injury. Organoids are relatively simple in vitro models, which could mimic the pathological changes of corresponding organs. In this study, we constructed a 3D testicular organoid model using primary testicular cells from adult BALB/c mice. Similar to the testis, this organoid system has a blood-testis barrier (BTB)-like structure and could synthesize testosterone. ZIKV tropism of testicular cells and ZIKV-induced pathological changes in testicular organoid was also similar to that in mammalian testis. Therefore, our results provide a simple and reproducible in vitro testicular model for the investigations of ZIKV-induced testicular injury.