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Asymmetric inheritance of centrosomes maintains stem cell properties in human neural progenitor cells.
During human forebrain development, neural progenitor cells (NPCs) in the ventricular zone (VZ) undergo asymmetric cell divisions to produce a self-renewed progenitor cell, maintaining the potential to go through additional rounds of cell divisions, and differentiating daughter cells, populating the developing cortex. Previous work in the embryonic rodent brain suggested that the preferential inheritance of the pre-existing (older) centrosome to the self-renewed progenitor cell is required to maintain stem cell properties, ensuring proper neurogenesis. If asymmetric segregation of centrosomes occurs in NPCs of the developing human brain, which depends on unique molecular regulators and species-specific cellular composition, remains unknown. Using a novel, recombination-induced tag exchange-based genetic tool to birthdate and track the segregation of centrosomes over multiple cell divisions in human embryonic stem cell-derived regionalised forebrain organoids, we show the preferential inheritance of the older mother centrosome towards self-renewed NPCs. Aberration of asymmetric segregation of centrosomes by genetic manipulation of the centrosomal, microtubule-associated protein Ninein alters fate decisions of NPCs and their maintenance in the VZ of human cortical organoids. Thus, the data described here use a novel genetic approach to birthdate centrosomes in human cells and identify asymmetric inheritance of centrosomes as a mechanism to maintain self-renewal properties and to ensure proper neurogenesis in human NPCs.
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Emerging Human Pluripotent Stem Cell-Based Human-Animal Brain Chimeras for Advancing Disease Modeling and Cell Therapy for Neurological Disorders.
Human pluripotent stem cell (hPSC) models provide unprecedented opportunities to study human neurological disorders by recapitulating human-specific disease mechanisms. In particular, hPSC-based human-animal brain chimeras enable the study of human cell pathophysiology in vivo. In chimeric brains, human neural and immune cells can maintain human-specific features, undergo maturation, and functionally integrate into host brains, allowing scientists to study how human cells impact neural circuits and animal behaviors. The emerging human-animal brain chimeras hold promise for modeling human brain cells and their interactions in health and disease, elucidating the disease mechanism from molecular and cellular to circuit and behavioral levels, and testing the efficacy of cell therapy interventions. Here, we discuss recent advances in the generation and applications of using human-animal chimeric brain models for the study of neurological disorders, including disease modeling and cell therapy.
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Brains and where else? Mapping theories of consciousness to unconventional embodiments.
It is assumed that a useful theory of consciousness (ToC) will explain why consciousness is associated with brains. However, the findings of evolutionary biology, developmental bioelectricity and synthetic bioengineering reveal ancient pre-neural roots of many mechanisms and algorithms occurring in brains: minds may have preceded brains. Most work in the emerging field of diverse intelligence emphasizes externally observable problem-solving competencies in unconventional media, such as cells, tissues and life-technology chimeras. Here, we inquire about the implications of these developments for ToCs. Specifically, we analyse popular current ToCs to ask: What features of each theory specifically pick out brains as a privileged substrate of inner perspective, or do the features emphasized by the theory occur elsewhere? We find that the operations and functional principles of most ToCs are not confined to neural substrates, and that the focus on brains is more driven by convention than by the specific content of existing ToCs. Encouragingly, several contemporary theorists have made explicit efforts to apply their theories to synthetic systems in light of recent technological developments in artificial intelligence and organoid bioengineering. We suggest that the science of consciousness should remain open to minds in unconventional embodiments. This article is part of the theme issue 'World models in natural and artificial intelligence'.
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Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates.
The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can strive to answer in addition to the technical ability to answer them. However, the tridimensional human stem cell-derived organoid system provides the unique opportunity to model human development and mimic the diverse cellular composition of human organs. This strategy is adaptable and malleable, and these neural organoids possess the morphogenic sensitivity to be patterned in various ways to generate the different regions of the human brain. Furthermore, recapitulating human development provides a platform for disease modeling. One master regulator of human neurodevelopment in many regions of the human brain is sonic hedgehog (SHH), whose expression gradient and pathway activation are responsible for conferring ventral identity and shaping cellular phenotypes throughout the neural axis. This review first discusses the benefits, challenges, and limitations of using organoids for studying human neurodevelopment and disease, comparing advantages and disadvantages with other in vivo and in vitro model systems. Next, we explore the range of control that SHH exhibits on human neurodevelopment, and the application of SHH to various stem cell methodologies, including organoids, to expand our understanding of human development and disease. We outline how this strategy will eventually bring us much closer to uncovering the intricacies of human neurodevelopment and biology.
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Models for evaluating glioblastoma invasion along white matter tracts.
White matter tracts (WMs) are one of the main invasion paths of glioblastoma multiforme (GBM). The lack of ideal research models hinders our understanding of the details and mechanisms of GBM invasion along WMs. To date, many potential in vitro models have been reported; nerve fiber culture models and nanomaterial models are biocompatible, and the former have electrically active neurons. Brain slice culture models, organoid models, and microfluidic chip models can simulate the real brain and tumor microenvironment (TME), which contains a variety of cell types. These models are closer to the real in vivo environment and are helpful for further studying not only invasion along WMs by GBM, but also perineural invasion and brain metastasis by solid tumors.
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SPG11 models reveal lysosomal calcium regulation of neural progenitor proliferation.
Lysosome dysfunction has been widely implicated in many models of neurodegeneration, but much less is understood of its involvement during brain development in health and disease. Hereditary spastic paraplegia caused by mutations in the SPG11 gene is a neurodegenerative disorder characterized by lysosome dysfunction, which also presents neurodevelopmental alterations. Using knockout mouse and cortical organoid models derived from induced pluripotent stem cells, we show that lysosome dysfunction caused by SPG11 mutations decreases the proliferation of neural progenitor cells at early stages of cortical development. At the cellular level, SPG11 mutations cause accumulation of calcium in lysosomes, which reduces proliferation of neural progenitor cells and diminishes apical tight junctions. RNA sequencing analysis revealed that these phenotypes in SPG11 organoids are caused by hypoactivation of mammalian target of rapamycin (mTOR) signaling. The latter is a consequence of lysosomal recruitment of the enzyme PI4K2A (phosphatidylinositol 4-kinase type 2 alpha) resulting in higher levels of its product PI(4)P (phosphatidylinositol-4-phosphate), a described regulator of the mTOR pathway. Pharmacological modulation of the function of the lysosomal calcium channel TRPML1 successfully corrected all developmental phenotypes in cortical organoids, highlighting the critical role of lysosomal calcium in signaling during the early phase of cortical development.
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Interpretable Multi-Feature Optical Analysis for Stage- and Batch-Aware Quality Assessment of Brain-Organoid Cultures.
Reliable quality assessment of brain organoids is important for reproducible culture and downstream experimentation, yet routine evaluation relies largely on qualitative brightfield inspection. We investigated whether visual QA criteria could be represented by interpretable image descriptors while accounting for developmental stage and culture batch. We analyzed 692 brightfield image-ROI pairs from six culture batches. Binary QA labels were assigned by one expert. We compared 115 handcrafted features with simple morphology and frozen pretrained DINOv2 and ResNet-50 representations using logistic-regression and random-forest classifiers. Leave-one-batch-out (LOBO) testing was the primary exploratory evaluation; repeated image-level cross-validation and maturation-only analyses provided complementary assessments. Handcrafted logistic regression achieved a pooled LOBO ROC AUC of 0.836 (conditional 95% batch bootstrap interval 0.625-0.960), with substantial variation among held-out batches. Mean repeated-CV AUC was 0.933 across all stages and 0.895 within maturation. At a fixed 0.5 score cutoff, all-stage LOBO sensitivity was 0.656 and specificity was 0.869. The comparison concerns the evaluated frozen-feature pipelines and does not establish superiority over fine-tuned deep learning. These results provide an exploratory image-analysis baseline for brightfield QA; label reproducibility and performance beyond the observed laboratory workflow require further validation.
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NRXN1 haploinsufficiency converges on RNA processing during cortical development, with partial transcriptomic concordance in adult autism cortex.
BACKGROUND: NRXN1 deletions are recurrent genetic risk factors for autism spectrum disorder (ASD), yet most functional work has focused on synaptic mechanisms. We asked whether NRXN1 haploinsufficiency is also associated with earlier gene-regulatory programs during cortical development, and whether related signals are detectable in adult ASD cortex. METHODS: We reanalyzed two public single-cell datasets: matched control and NRXN1-heterozygous cortical organoid samples (GSE228315; 215,442 cells, 26 samples) and post-mortem adult ASD cortex (Velmeshev et al., 2019; 104,559 nuclei, 31 donors). All comparisons were performed at the sample or donor level. RESULTS: In adult ASD cortex, donor-level analyses revealed no significant cell-type composition or CellRank-based fate-commitment differences. In organoids, paired pseudobulk comparisons identified 282 genes consistently downregulated across three or more neural cell types in NRXN1-heterozygous samples (10.6-fold enrichment, permutation p < 0.001). Robustness analyses-leave-one-gene-out, threshold-sensitivity, threshold-free consistency scoring, and unbiased GO/Reactome enrichment-supported a broad RNA-processing signal, with mRNA nuclear export and splicing prominently affected (Reactome "Metabolism of RNA" FDR = 3 × 10-10). In the same adult cohort, 8 of 16 cell types showed directional concordance under unmatched tests, but none exceeded an expression-matched permutation null after correction (0/16). CONCLUSIONS: NRXN1 haploinsufficiency is associated with coordinated downregulation of RNA-processing genes in cortical organoids. Cross-dataset concordance with adult ASD cortex is directional but not specific to NRXN1, and the convergence on mRNA nuclear export and RNA-processing genes should be interpreted cautiously and verified by direct experimental perturbation.
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Modeling the Interaction between the Microenvironment and Tumor Cells in Brain Tumors.
Despite considerable recent advances in understanding and treating many other cancers, malignant brain tumors remain associated with low survival or severe long-term sequelae. Limited progress, including development of immunotherapies, relates in part to difficulties in accurately reproducing brain microenvironment with current preclinical models. The cellular interactions among resident microglia, recruited tumor-associated macrophages, stromal cells, glial cells, neurons, and cancer cells and how they affect tumor growth or behavior are emerging, yet many questions remain. The role of the blood-brain barrier, extracellular matrix components, and heterogeneity among tumor types and within different regions of a single tumor further complicate the matter. Here, we focus on brain microenvironment features impacted by tumor biology. We also discuss limits of current preclinical models and how complementary models, such as humanized animals and organoids, will allow deeper mechanistic insights on cancer biology, allowing for more efficient testing of therapeutic strategies, including immunotherapy, for brain cancers.
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Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer's disease.
INTRODUCTION: Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. METHODS: We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single-cell RNA-sequencing data from HHV-infected forebrain organoids to investigate HHV-infection-associated transposable element (TE) dysregulation underlying AD etiologies. RESULTS: We identified widespread TE dysregulation in HHV-positive human AD brains, including an astrocyte-specific upregulation of LINE1 subfamily TEs in HHV-positive human AD brains. We further pinpointed astrocyte-specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long-range enhancer-promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti-HHV drugs (valacyclovir and acyclovir) in a virus-infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau-associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model. DISCUSSION: Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation. HIGHLIGHTS: Via analysis of bulk RNA-seq data in two large-scale human brain biobanks, ROS/MAP (n = 109 pathologically confirmed AD and n = 44 cognitively healthy controls) and MSBB (n = 284 AD and n = 150 cognitively healthy controls), we identified widespread TE activation in HHV-positive human AD brains and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score, and CERAD score. We identified cell type-specific LINE1 upregulation in both microglia and astrocytes of human AD brains via long-range enhancer-promoter chromatin interactions on lncRNA nuclear enriched abundant transcript 1 (NEAT1). We determined that usage of valacyclovir and acyclovir was significantly associated with reduced incidence of AD in a large real-world patient database. Using the HEK293 tau P301S model and U2OS mt-Keima cell model, we determined that valacyclovir treatment rescued tau-associated neuropathology and alleviated activation of LINE1 with increased cellular autophagy-level mechanistically supported clinical benefits of valacyclovir in real-world patient data.