stLearn: integrating spatial location, tissue morphology and gene expression to find cell types, cell-cell interactions and spatial trajectories within undissociated tissues

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: May 31, 2020

ABSTRACT Spatial Transcriptomics is an emerging technology that adds spatial dimensionality and tissue morphology to the genome-wide transcriptional profile of cells in undissociated tissue. Integrating these three types data creates a vast potential for deciphering novel biology cell their native morphological context. Here we developed innovative integrative analysis approaches utilise all first find types, then reconstruct type evolution within tissue, search regions with high cell-to-cell interactions. First, normalisation gene expression, compute distance measure using similarity neighbourhood smoothing. The normalised used clusters represent profiles specific cellular phenotypes. Clusters are further sub-clustered if spatially separated. Analysing anatomical mouse brain sections 12 human datasets, found clustering method more accurate sensitive than other methods. Second, introduce calculate states by pseudo-space-time (PST) distance. PST function physical (spatial distance) expression (pseudotime estimate pairwise between among We transition gradients connected locally cluster, or globally clusters, directed minimum spanning tree optimisation approach algorithm could model from non-invasive invasive breast cancer dataset. Third, information identify locations where there both ligand-receptor interaction activity diverse co-localisation. These predicted be hotspots cell-cell interactions likely occur. detected pairs significantly enriched compared background distribution across Together, algorithms, implemented comprehensive Python software stLearn, allow elucidation biological processes healthy diseased tissues.

Language: Английский

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Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(7), P. 1597 - 1616

Published: Jan. 15, 2021

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed determine the contribution of microglia neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion (FPI) in male mice cortical neuropathology/inflammation was assessed using mRNA panel. Gene expression associated inflammation robustly increased acutely (1 majority independent. At 7 30 dpi, however, microglial depletion reversed TBI-related genes inflammation, interferon signaling, neuropathology. Myriad suppressed endpoints attributed neurons. To understand relationship between microglia, neurons, other glia, single-cell RNA sequencing completed critical point evolution from pathogenesis. Cortical exhibited distinct TBI-associated clustering type-1 neurodegenerative/damage-related genes. In dopamine long-term potentiation, calcium synaptogenesis suppressed. Microglial these neuronal alterations. Furthermore, there reduced dendritic complexity connectively cognitive impairment dpi. All functional behavioral impairments prevented by depletion. Collectively, studies indicate that promote persistent homeostasis TBI.SIGNIFICANCE STATEMENT Millions traumatic injuries (TBIs) occur United States alone each year. Survivors face elevated rates psychiatric complications long inciting Recent human link neuroinflammation adverse neurologic outcomes, suggesting evolving inflammatory may be an opportunity for intervention. Here, eliminate compare effects diffuse TBI on neurons presence absence microglia-mediated inflammation. do not undergo TBI-induced changes gene transcription or structure. elimination (dpi). have role disrupting TBI, particularly timepoints.

Language: Английский

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Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Sept. 10, 2020

Abstract Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model TBI that mild forms trauma severe deficits meningeal lymphatic drainage begin within hours last out to at least one month post-injury. To investigate mechanism underlying impaired function TBI, examined how increased intracranial pressure (ICP) influences the lymphatics. We ICP can contribute dysfunction. Moreover, show pre-existing dysfunction before leads neuroinflammation negative cognitive outcomes. Finally, report rejuvenation aged mice ameliorate TBI-induced gliosis. These findings provide insights into both causes consequences suggest therapeutics targeting system may offer strategies treat TBI.

Language: Английский

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To Kill a Microglia: A Case for CSF1R Inhibitors

Trends in Immunology, Journal Year: 2020, Volume and Issue: 41(9), P. 771 - 784

Published: Aug. 10, 2020

Language: Английский

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Microglia in the Neuroinflammatory Pathogenesis of Alzheimer’s Disease and Related Therapeutic Targets

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: April 26, 2022

Alzheimer's disease (AD) is the most prevalent neurodegenerative worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment AD has been only partially successful as majority pharmacotherapies on market may alleviate some symptoms. In occurrence AD, increasing attention paid neurodegeneration, while resident glial cells, like microglia are also observed. Microglia, a kind crucial cells associated with innate immune response, functions double-edge sword role in CNS. They exert beneficial detrimental influence adjacent neurons through secretion both pro-inflammatory cytokines well neurotrophic factors. addition, their endocytosis debris toxic protein Aβ tau ensures homeostasis neuronal microenvironment. this review, we will systematically summarize recent research regarding roles pathology latest microglia-associated therapeutic targets mainly including genes, anti-inflammatory genes phagocytosis at length, which contradictory controversial warrant further be investigated.

Language: Английский

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Robust mapping of spatiotemporal trajectories and cell–cell interactions in healthy and diseased tissues

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 25, 2023

Spatial transcriptomics (ST) technologies generate multiple data types from biological samples, namely gene expression, physical distance between points, and/or tissue morphology. Here we developed three computational-statistical algorithms that integrate all to advance understanding of cellular processes. First, present a spatial graph-based method, pseudo-time-space (PSTS), model and uncover relationships transcriptional states cells across tissues undergoing dynamic change (e.g. neurodevelopment, brain injury microglia activation, cancer progression). We further spatially-constrained two-level permutation (SCTP) test study cell-cell interaction, finding highly interactive regions thousands ligand-receptor pairs with markedly reduced false discovery rates. Finally, imputation method neural network (stSME), correct for technical noise/dropout increase ST coverage. Together, the developed, implemented in comprehensive fast stLearn software, allow robust interrogation processes within healthy diseased tissues.

Language: Английский

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Activated microglia mitigate Aβ-associated tau seeding and spreading

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(8)

Published: June 8, 2021

In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well seeding spreading of tau aggregates. Whether this Aβ-enhanced seeding/spreading is due to loss microglial function or a toxic gain TREM2-deficient microglia unclear. Depletion mice with established brain amyloid has no effect on but results less spine neuronal loss. Microglial repopulation aged improved cognitive deficits. context pathology, we asked whether removal decreased Aβ-driven spreading. We show that both TREM2KO ablation dramatically enhance around plaques. Interestingly, although repopulated clustered plaques, they had reduction disease-associated (DAM) expression elevated seeding/spreading. Together, these data suggest TREM2-dependent activation DAM phenotype essential delaying Aβ-induced pathological propagation.

Language: Английский

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Role of IL-6 in the regulation of neuronal development, survival and function

Cytokine, Journal Year: 2021, Volume and Issue: 144, P. 155582 - 155582

Published: May 29, 2021

The pleiotropic cytokine interleukin-6 (IL-6) is emerging as a molecule with both beneficial and destructive potentials. It can exert opposing actions triggering either neuron survival after injury or causing neurodegeneration cell death in neurodegenerative neuropathic disorders. Importantly, neurons respond differently to IL-6 this critically depends on their environment whether they are located the peripheral central nervous system. In addition its hub regulator role inflammation, recently an important of function health disease, offering exciting possibilities for more mechanistic insight into pathogenesis mental, pain disorders developing novel therapies diseases neuroimmune neurogenic pathogenic components.

Language: Английский

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Microglial/Macrophage polarization and function in brain injury and repair after stroke

CNS Neuroscience & Therapeutics, Journal Year: 2021, Volume and Issue: 27(5), P. 515 - 527

Published: March 1, 2021

Abstract Stroke is a leading cause of disability and mortality, with limited treatment options. After stroke injury, microglia CNS‐resident macrophages are rapidly activated regulate neuropathological processes to steer the course functional recovery. To accelerate this recovery, can engulf dying cells clear irreparably‐damaged tissues, thereby creating microenvironment that more suitable for formation new neural circuitry. In addition, monocyte‐derived cross compromised blood‐brain barrier infiltrate injured brain. The specific functions myeloid lineage in brain injury repair diverse dependent on phenotypic polarization statuses. However, it remains be determined what degree CNS‐invading occupy different niches from microglia. review, we describe physiological characteristics developing adult We also review (a) activation after stroke, (b) molecular mechanisms control status, (c) contribution pathology versus repair. Finally, summarize current breakthroughs therapeutic strategies calibrate microglia/macrophage responses stroke.

Language: Английский

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Temporal and spatial cellular and molecular pathological alterations with single-cell resolution in the adult spinal cord after injury

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 2, 2022

Spinal cord injury (SCI) involves diverse responses in different cell types a temporally and spatially specific manner. Here, using single-cell transcriptomic analyses combined with classic anatomical, behavioral, electrophysiological analyses, we report, resolution, temporal molecular cellular changes crush-injured adult mouse spinal cord. Data revealed pathological of 12 major types, three which infiltrated into the at distinct times post-injury. We discovered novel microglia astrocyte subtypes uninjured cord, their dynamic conversions additional stage-specific subtypes/states. Most occur 3-days post-injury by day-14 second wave microglial activation emerged, accompanied various including neurons, indicative round attacks. By day-38, are still substantially deviated from states, demonstrating prolonged alterations. This study provides comprehensive mapping cellular/molecular along axis after SCI, may facilitate development therapeutic strategies, those targeting microglia.

Language: Английский

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