Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 28, 2024

Abstract The ability to spatially map multiple layers of the omics information over different time points allows for exploring mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC–RNA–Protein-seq) CTRP-seq CUT&Tag– RNA–Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) dynamic remodeling development neuroinflammation. A spatiotemporal atlas mouse was obtained at stages from postnatal day P0 P21, compared regions interest human developing brains. Specifically, cortical area, discovered temporal persistence spreading chromatin accessibility layer-defining transcription factors. In corpus callosum, observed priming myelin genes across subregions. Together, it suggests a role layer specific projection neurons coordinate axonogenesis myelination. We further mapped lysolecithin (LPC) neuroinflammation model common molecular programs Microglia, exhibiting both conserved distinct inflammation resolution, are transiently activated not only core LPC lesion, but also distal locations presumably through neuronal circuitry. Thus, this work unveiled differential neuroinflammation, resulting valuable data resource investigate function

Язык: Английский

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Neurodegeneration and demyelination in multiple sclerosis

Neuron, Год журнала: 2024, Номер unknown

Опубликована: Июнь 1, 2024

Язык: Английский

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Inflammatory microglia correlate with impaired oligodendrocyte maturation in multiple sclerosis

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 14, 2025

Introduction Remyelination of demyelinated axons can occur as an endogenous repair mechanism in multiple sclerosis (MS), but its efficacy varies between both MS individuals and lesions. The molecular cellular mechanisms that drive remyelination remain poorly understood. Here, we studied the relation microglia activation activity MS. Methods We correlated regenerative (CD163 + ) inflammatory (iNOS with BCAS1 oligodendrocytes, subdivided into early-stage (<3 processes) late-stage (≥3 cells brain donors high or low remyelinating potential remyelinated lesions active ramified/amoeboid (non-foamy) foamy microglia. A cohort categorized efficiently (ERDs; n=25) (PRDs; n=17) was included, based on their proportion at autopsy. Results discussion hypothesized more CD163 oligodendrocytes non-foamy from ERDs iNOS fewer PRDs. For microglia, however, no differences were observed donor groups. In line our hypothesis, found INOS significantly increased PRDs compared to within lesions, detected comparison Although for did find vs Interestingly, a positive correlation identified presence oligodendrocytes. These findings suggest impaired maturation encountering may underlie deficits unsuccessful lesion

Язык: Английский

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4D marmoset brain map reveals MRI and molecular signatures for onset of multiple sclerosis–like lesions

Science, Год журнала: 2025, Номер 387(6737)

Опубликована: Фев. 27, 2025

Inferring cellular and molecular dynamics of multiple sclerosis (MS) lesions from postmortem tissue collected decades after onset is challenging. Using magnetic resonance image (MRI)-guided spatiotemporal RNA profiling in marmoset experimental autoimmune encephalitis (EAE), we mapped lesion modeled perturbations relevant to MS. Five distinct microenvironments emerged, involving neuroglial responses, destruction repair, brain border regulation. Before demyelination, MRI identified a high ratio proton density-weighted signal T1 relaxation time, capturing early hypercellularity, elevated astrocytic ependymal senescence signals marked perivascular periventricular areas that later became demyelination hotspots. As expanded, concentric glial barriers formed, initially dominated by proliferating diversifying microglia oligodendrocyte precursors, replaced monocytes lymphocytes. We highlight SERPINE1+ astrocytes as signaling hub underlying both EAE

Язык: Английский

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Optimizing Xenium In Situ data utility by quality assessment and best-practice analysis workflows

Nature Methods, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Abstract The Xenium In Situ platform is a new spatial transcriptomics product commercialized by 10x Genomics, capable of mapping hundreds genes in situ at subcellular resolution. Given the multitude commercially available technologies, recommendations choice and analysis guidelines are increasingly important. Herein, we explore 25 datasets generated from multiple tissues species, comparing scalability, resolution, data quality, capacities limitations with eight other spatially resolved technologies commercial platforms. addition, benchmark performance open-source computational tools, when applied to datasets, tasks including preprocessing, cell segmentation, selection variable features domain identification. This study serves as an independent Xenium, provides best practices for such datasets.

Язык: Английский

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Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis

Immunity, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation prominent in ALS, but the cell state dynamics pathways driving remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords identified altered glial states, including increased expression inflammatory activation markers. Many these signals converged on inflammation death regulator receptor-interacting protein kinase 1 (RIPK1) necroptotic pathway. In superoxide dismutase (SOD1)G93A mice, blocking RIPK1 activity delayed symptom onset impairment modulated responses. used human induced pluripotent stem (iPSC)-derived neuron, astrocyte, microglia tri-cultures to identify potential biomarkers that are secreted upon vitro inhibition cerebrospinal fluid (CSF) people with ALS. These data reveal ALS-enriched populations associated suggest deleterious role for neuroinflammatory signaling pathogenesis.

Язык: Английский

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Spatially resolved gene signatures of white matter lesion progression in multiple sclerosis

Nature Neuroscience, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 5, 2024

Язык: Английский

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Spatial Transcriptomics: Biotechnologies, Computational Tools, and Neuroscience Applications

Small Methods, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Spatial transcriptomics (ST) represents a revolutionary approach in molecular biology, providing unprecedented insights into the spatial organization of gene expression within tissues. This review aims to elucidate advancements ST technologies, their computational tools, and pivotal applications neuroscience. It is begun with historical overview, tracing evolution from early image-based techniques contemporary sequence-based methods. Subsequently, methods essential for data analysis, including preprocessing, cell type annotation, clustering, detection spatially variable genes, cell-cell interaction 3D multi-slices integration are discussed. The central focus this application neuroscience, where it has significantly contributed understanding brain's complexity. Through ST, researchers advance brain atlas projects, gain development, explore neuroimmune dysfunctions, particularly tumors. Additionally, enhances neuronal vulnerability neurodegenerative diseases like Alzheimer's neuropsychiatric disorders such as schizophrenia. In conclusion, while already profoundly impacted challenges remain issues enhancing sequencing technologies developing robust tools. underscores transformative potential paving way new therapeutic research.

Язык: Английский

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Towards the Next Generation of Data‐Driven Therapeutics Using Spatially Resolved Single‐Cell Technologies and Generative AI

European Journal of Immunology, Год журнала: 2025, Номер 55(2)

Опубликована: Фев. 1, 2025

ABSTRACT Recent advances in multi‐omics and spatially resolved single‐cell technologies have revolutionised our ability to profile millions of cellular states, offering unprecedented opportunities understand the complex molecular landscapes human tissues both health disease. These developments hold immense potential for precision medicine, particularly rational design novel therapeutics treating inflammatory autoimmune diseases. However, vast, high‐dimensional data generated by these present significant analytical challenges, such as distinguishing technical variation from biological or defining relevant questions that leverage added spatial dimension improve understanding tissue organisation. Generative artificial intelligence (AI), specifically variational autoencoder‐ transformer‐based latent variable models, provides a powerful flexible approach addressing challenges. models make inferences about cell's intrinsic state effectively identifying patterns, reducing dimensionality modelling variability datasets. This review explores current landscape technologies, application generative AI analysis their transformative impact on By combining with advanced methodologies, we highlight insights into pathogenesis disorders outline future directions leveraging achieve goal AI‐powered personalised medicine.

Язык: Английский

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The deubiquitinase OTUD7B ameliorates central nervous system autoimmunity by inhibiting degradation of glial fibrillary acidic protein and astrocyte hyperinflammation

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 27, 2025

Astrocytes are central to the pathogenesis of multiple sclerosis; however, their regulation by intrinsic post-translational ubiquitination and deubiquitination is unresolved. This study shows that deubiquitinating enzyme OTUD7B in astrocytes confers protection against murine experimental autoimmune encephalomyelitis, a model MS, limiting neuroinflammation. RNA-sequencing isolated spatial transcriptomics showed EAE downregulates expression chemokines inflammatory lesions, which associated with reduced recruitment encephalitogenic CD4 + T cells. Furthermore, was essential for GFAP protein bordering lesions. Mechanistically, (i) restricted TNF-induced chemokine production sequential K63- K48-deubiquitination RIPK1 NF-κB MAPK activation (ii) enabled supporting mRNA preventing its proteasomal degradation through GFAP. dual action on TNF signaling identifies astrocyte-intrinsic as inhibitor astrocyte-mediated inflammation.

Язык: Английский

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