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ASPEN: Robust detection of allelic dynamics in single cell RNA-seq.
Single-cell RNA-seq data from F1 hybrids provide a unique framework for dissecting complex regulatory mechanisms, but allelic measurements are limited by technical noise due to low counts. Here, we present ASPEN, a statistical method for modeling allelic mean and variance in single-cell transcriptomic data. ASPEN combines a sensitive mapping pipeline with a moderated beta-binomial model and adaptive shrinkage to distinguish allelic imbalance and changes to allelic variance in single cells. In both simulated and empirical datasets, ASPEN achieves a ~30% increase in sensitivity over existing approaches for single-cell allelic imbalance detection. Applied to mouse brain organoids and T cells, ASPEN identifies genes with incomplete X inactivation, random monoallelic expression, and significant deviations in allelic variance. These results reveal reduced variance in essential genes, consistent with tight regulatory control, and increased variance at neurodevelopmental and immune loci, indicative of regulatory flexibility.
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Neurodevelopmental Implications Underpinning Hereditary Spastic Paraplegia.
BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of rare genetic neurodegenerative disorders characterized by corticospinal tract abnormalities. But frequently, abnormalities of proteins implicated in HSP have been identified in brain disorders of childhood, raising the possibility that early brain developmental mechanism underlying HSP. RESULTS AND CONCLUSIONS: Here we summarized the clinical features of 89 HSP subtypes and found most have onset of symptoms earliest reported in infancy or early childhood. Importantly, HSP patients showed early brain developmental related phenotypes such as microcephaly, ventricular enlargement, and corpus callosum dysplasia. In addition, the expression trajectories analysis showed HSP genes were diffusely expressed across all human prenatal cortical regions and most genes enriched from post-conception weeks 8-24, periods characterized by neuro progenitor proliferation and neurogenesis. Furthermore, studies utilizing patient derived induced pluripotent stem cells (iPSCs)/organoids and mouse models have suggested that most HSP proteins play either direct or indirect roles in the development of the central nervous system. Therefore, HSP possesses a neurodevelopmental aspect and is not merely a degenerative disease, which may aid in better understanding the pathogenesis of this disease.
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Embryonic Stem Cell-Derived Neurons as a Model System for Epigenome Maturation during Development.
DNA methylation in neurons is directly linked to neuronal genome regulation and maturation. Unlike other tissues, vertebrate neurons accumulate high levels of atypical DNA methylation in the CH sequence context (mCH) during early postnatal brain development. Here, we investigate to what extent neurons derived in vitro from both mouse and human pluripotent stem cells recapitulate in vivo DNA methylation patterns. While human ESC-derived neurons did not accumulate mCH in either 2D culture or 3D organoid models even after prolonged culture, cortical neurons derived from mouse ESCs acquired in vivo levels of mCH over a similar time period in both primary neuron cultures and in vivo development. mESC-derived neuron mCH deposition was coincident with a transient increase in Dnmt3a, preceded by the postmitotic marker Rbfox3 (NeuN), was enriched at the nuclear lamina, and negatively correlated with gene expression. We further found that methylation patterning subtly differed between in vitro mES-derived and in vivo neurons, suggesting the involvement of additional noncell autonomous processes. Our findings show that mouse ESC-derived neurons, in contrast to those of humans, can recapitulate the unique DNA methylation landscape of adult neurons in vitro over experimentally tractable timeframes, which allows their use as a model system to study epigenome maturation over development.
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Rotenone exerts developmental neurotoxicity in a human brain spheroid model.
Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and NT assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predict and study human toxicity. By combining these technologies, we generated multicellular brain spheroids (BrainSpheres) from human iPSC. The model has previously shown to be reproducible and recapitulates several neurodevelopmental features. Our results indicate, rotenone's toxic potency varies depending on the differentiation status of the cells, showing higher reactive oxygen species (ROS) and higher mitochondrial dysfunction during early than later differentiation stages. Immuno-fluorescence morphology analysis after rotenone exposure indicated dopaminergic-neuron selective toxicity at non-cytotoxic concentrations (1 μM), while astrocytes and other neuronal cell types were affected at (general) cytotoxic concentrations (25 μM). Omics analysis showed changes in key pathways necessary for brain development, indicating rotenone as a developmental neurotoxicant and show a possible link between previously shown effects on neurite outgrowth and presently observed effects on Ca2+ reabsorption, synaptogenesis and PPAR pathway disruption. In conclusion, our BrainSpheres model has shown to be a reproducible and novel tool to study neurotoxicity and developmental neurotoxicity. Results presented here support the idea that rotenone can potentially be a developmental neurotoxicant.
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The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.
Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in the brain, with glial cell-derived EVs increasingly recognized for their roles in maintaining brain homeostasis and contributing to the progression of neurodegenerative diseases. By transferring a diverse cargo of bioactive molecules, including proteins, RNAs, and organelles, EVs influence recipient cell behavior and overall brain function. In neurodegenerative conditions, glial EVs can either propagate pathogenic signals or deliver neuroprotective and regenerative cues, depending on their cellular origin and molecular composition. This context-dependent heterogeneity highlights the need for physiologically relevant human models to investigate EVs biology. Human induced pluripotent stem cell (iPSC)-derived glial models provide a disease-relevant platform, as they recapitulate key pathological features of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). When further integrated with brain organoid platforms, these iPSC-based systems enable the generation of three-dimensional environments that closely resemble in vivo EVs dynamics. Importantly, glial EVs can modulate cellular pathways involved in neuronal survival and function. Indeed, their potential to interact with and, under specific experimental conditions, traverse the blood-brain barrier (BBB) has contributed to growing interest in their application for biomarker discovery and therapeutic development. Engineered and patient-specific EVs derived from iPSCs are emerging as promising tools for targeted, cell type-specific, therapeutic approaches, although their clinical applicability still requires further validation. This review discusses the emerging evidence supporting the dual role of iPSC-derived glial EVs in health and disease, underscores the translational potential of iPSC-based platforms for mechanistic studies, and outlines their promise as precision medicine tools for diagnostics and therapy.
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Modeling blood-brain barrier-glioblastoma interactions: implications for chemoresistance and therapeutic targeting.
Glioblastoma (GBM) is the most aggressive and common primary brain tumor in adults and remains associated with a dismal prognosis despite standard-of-care treatment. A major contributor to therapeutic failure is the blood-brain barrier (BBB), which severely restricts the penetration of most therapeutic agents into the brain. In addition, the complex and dynamic interactions between GBM and its surrounding microenvironment, including the BBB, remain incompletely understood, largely due to limitations of existing experimental models. In this review, we outline the key anatomical and physiological features of the BBB and examine how its disruption in the peritumoral region and within GBM contributes to drug resistance. We then provide a critical comparison of current in vitro and in vivo models of the BBB-GBM interface, ranging from static culture systems to dynamic platforms and animal models, highlighting their respective strengths and limitations in recapitulating the tumor microenvironment and predicting drug delivery in human tumors. Particular attention is given to the extent to which these models capture vascular heterogeneity, cellular crosstalk, and barrier plasticity. Overall, this review integrates static and dynamic in vitro approaches with in vivo animal models to provide a comprehensive framework for understanding BBB-GBM interactions and their role in chemoresistance. Such models are essential for elucidating tumor-extrinsic mechanisms of drug resistance, identifying novel therapeutic targets, and improving the predictive value of preclinical studies. Notably, organoid-based BBB models emerge as highly promising dynamic platforms, as they more faithfully recapitulate the three-dimensional architecture, cellular heterogeneity, and microenvironmental interactions of GBM. Continued refinement of physiologically relevant models will be critical to accelerating the translation of effective therapeutic strategies into clinical practice.
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Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function.
Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination, and therefore is of interest as a therapeutic in demyelinating diseases such as multiple sclerosis (MS). Here, we test whether metformin has a similar effect in human stem cell derived-OPCs. We assess how well human monoculture, organoid and chimera model culture systems simulate in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increases myelin proteins and/or sheaths in all models even when human cells remain fetal-like. In the chimera model, metformin leads to increased mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase of mitochondrial function/metabolism transcripts. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also express similar transcripts. Metformin's brain effect is thus not cell-specific, alters metabolism in part through mitochondrial changes and leads to more myelin production. This bodes well for clinical trials testing metformin for neuroprotection.
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Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice's cerebella.
Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells' neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum.
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In utero infection of Zika virus leads to abnormal central nervous system development in mice.
The World Health Organization has declared ZIKA virus (ZIKV) a global public health emergency, prompted by the association of ZIKV infections with severe brain abnormalities in the human fetus. ZIKV preferentially targets human neuronal precursor cells (NPCs) in both monolayer and cortical brain organoid culture systems and stunts their growth. Although ZIKV is well recognized to cause microcephaly, there is no systematic analysis to demonstrate the effect of ZIKV on central nervous system (CNS) development, including brain malformations and spinal cord dysfunction. Here, we conducted a longitudinal analysis to show that a novel mouse model (infected in utero and monitored after birth until adulthood) recapitulates the effects of ZIKV infection affecting neural stem cells fate and leads to a thinner cortex and a smaller brain. Furthermore, we demonstrate the effect of ZIKV on spinal cord function. Specifically, we found significant reductions in neuron numbers in the anterior horn of grey matter of the spinal cord and muscle dystrophy with a significant decrease in forepaw grip strength in the ZIKV group. Thus, the established mouse model of ZIKV infection leading to abnormal CNS development will help to further advance our understanding of the disease pathogenesis.
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Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion.
The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.