Integration of single-cell and bulk RNA sequencing data reveals key cell types and regulators in traumatic brain injury

Zheng, Ruizhe; Jin, Xing; Huang, Qiong; Yang, Xitao; Zhao, Changyi; Li, Xinyuan

doi:10.3934/mbe.2021065

Cited by 8 publications

(8 citation statements)

References 38 publications

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“…In addition to mediators directly implicated in neuroinflammation, we expanded our gene expression analyses to include Icam1 to investigate the contribution of microglia in cell-cell communication propagating peripheral inflammation to neuroinflammatory signals. Indeed, Icam1 has been reported to be elevated in vivo under different inflammatory conditions 61,62 ; our previous report and the current study indicate that these findings are extended to tumor-induced neuroinflammation. 37 This study indicates that microglia are implicated in tumor-induced elevations of Icam1 expression in the amygdala, but not the hippocampus.…”

Section: Discussionsupporting

confidence: 73%

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Strehle,

Otto‐Dobos,

Grant

et al. 2024

The FASEB Journal

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Following diagnosis but before treatment, up to 30% of breast cancer patients report behavioral side effects (e.g., anxiety, depression, memory impairment). Our rodent mammary tumor model recapitulates aspects of these behavioral sequelae, as well as elevated circulating and brain inflammatory mediators. Neuroinflammation is a proposed mechanism underlying the etiology of mood disorders and cognitive deficits, and therefore may be contributing to tumor‐associated behavioral side effects. The cellular mechanisms by which tumor‐induced neuroinflammation occurs remain unknown, making targeted treatment approaches inaccessible. Here, we tested the hypotheses that microglia are the primary cells driving tumor‐induced neuroinflammation and behavioral side effects. Young adult female BALB/c mice were induced with a 67NR mammary tumor; tumor‐free controls underwent a sham surgery. Mammary tumors increased IBA1+ and GFAP+ staining in the amygdala and hippocampus relative to tumor‐free controls. However, tumors did not alter gene expression of Percoll‐enriched microglia isolated from the whole brain. While cognitive, social, and anhedonia‐like behaviors were not altered in tumor‐bearing mice, tumors increased central tendency in the open‐field test; microglia depletion did not reverse this effect. Brain region RT‐qPCR data indicated that microglia depletion attenuated tumor‐induced elevations of neuroinflammatory gene expression in a region‐ and mediator‐specific manner. These results indicate a causal role of microglia in tumor‐induced neuroinflammation. This research advances our understanding of the cellular mechanisms underlying tumor‐induced neuroinflammation in order to understand how brain responses (e.g., behavior) may be altered with subsequent cancer‐related immune challenges.

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Section: Discussionsupporting

confidence: 73%

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Strehle,

Otto‐Dobos,

Grant

et al. 2024

The FASEB Journal

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“…Marked Aβ deposition causes the activation of perivascular macrophages/microglia that can build “cuff-like” structures around the Aβ-affected vessels. Recent studies pinpoint the existence of endothelial/microglial crosstalk via CSF1/CSF-1R signaling that regulates BBB integrity and systemic macrophage recruitment to the brain and interaction via Icam1–Itagm that activates integrin signaling pathways in both cell types ( Honarpisheh et al, 2020 ; Zhu et al, 2020 ; Delaney et al, 2021 ; Zheng et al, 2021 ). In addition, our results revealed the microvascular profile that favors the disease phenotype of microglial mirrored in the upregulation of TYROBP, TREM2, and Cst7 in both early and late stages of CAA vasculopathy.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profile of Blood–Brain Barrier Remodeling in Cerebral Amyloid Angiopathy

Situ

Citalán-Madrid

Stamatovic

et al. 2022

Front. Cell. Neurosci.

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Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by amyloid β (Aβ) peptide deposition within the walls of medium to small-caliber blood vessels, cerebral microhemorrhage, and blood–brain barrier (BBB) leakage. It is commonly associated with late-stage Alzheimer’s disease. BBB dysfunction is indicated as a pathological substrate for CAA progression with hyperpermeability, enhancing the extravasation of plasma components and inducing neuroinflammation, further worsening BBB injury and contributing to cognitive decline. Although significant effort has been made in defining the gene mutations and risk factors involved in microvascular alterations with vascular dementia and Alzheimer’s disease, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The present study aimed to elucidate the transcriptional profile of the cerebral microvessels (BBB) in a murine model with CAA vasculopathy to define potential causes and underlying mechanisms of BBB injury. A comprehensive RNA sequencing analysis was performed of CAA vasculopathy in Tg-SwDI mice at 6 and 18 months in comparison to age-matched wildtype controls to examine how age and amyloid accumulation impact the transcriptional signature of the BBB. Results indicate that Aβ has a critical role in triggering brain endothelial cell and BBB dysfunction in CAA vasculopathy, causing an intense proinflammatory response, impairing oxidative metabolism, altering the coagulation status of brain endothelial cells, and remodeling barrier properties. The proinflammatory response includes both adaptive and innate immunity, with pronounced induction of genes that regulate macrophage/microglial activation and chemokines/adhesion molecules that support T and B cell transmigration. Age has an important impact on the effects of Aβ, increasing the BBB injury in CAA vasculopathy. However, early inflammation, particularly microglia/macrophage activation and the mediators of B lymphocytes’ activities are underlying processes of BBB hyperpermeability and cerebral microbleeds in the early stage of CAA vasculopathy. These findings reveal a specific profile of the CAA-associated BBB injury that leads to a full progression of CAA.

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“…Some studies have shown the role of TYROBP + ECs in exacerbating malignant cell progression with a uniquely identi able metabolic and immunological cellular pro le 16 . Additionally, it is thought that microglia and ECs might actively interact through the Icam1-Il2rg and C1qa-Cd93, and microglia might also communicate with each other via Icam1-Itagm, elucidating the importance of this TYROBP pathway in disease-associated endothelial vasculature and the surrounding cellular microenvironment 17 . One of the key roles of TYROBP in AD is its association with microglial activation and the clearance of amyloid-beta plaques, which are a hallmark of AD pathology.…”

Section: Discussionmentioning

confidence: 99%

RNA Profiling of Brain Microvessels Reveals Altered Morphology and Signaling in a Mouse Model of Alzheimer's Disease

Naranjo,

Osborne,

Torices

et al. 2024

Preprint

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Disruptions in pericyte and endothelial cell expression can compromise the integrity of the blood-brain barrier (BBB), leading to neurovascular dysfunction and the development of neurological disorders. However, the study of microvessel RNAs has been limited to tissue homogenates, with spatial visualization only available for protein targets. We introduce an innovative microvessel isolation technique that is RNA-friendly for the purpose of coupling with RNAscope analysis. RNA-friendly microvessel isolation combined with RNAscope analysis enables the visualization of cell-specific RNA within the spatial and histological context of the BBB. Using this approach, we have gained valuable insights into the structural and functional differences associated with the microvessels of 5XFAD mice, a mouse model of Alzheimer’s disease (AD). RNAscope analysis revealed a decrease in pericytes from microvessels isolated from 5XFAD mice in comparison to wild-type mice. Additionally, the microvessels of 5XFAD mice exhibited an increase in TYROBP mRNA expression. These findings significantly advance our understanding of neurovascular interactions and hold great promise for guiding the development of targeted therapeutic interventions. This innovative approach enables visualization of cell RNA while preserving the spatial and histological context of the BBB, shedding light on the mechanisms underlying neurovascular unit communication.

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Integration of single-cell and bulk RNA sequencing data reveals key cell types and regulators in traumatic brain injury

Cited by 8 publications

References 38 publications

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Transcriptomic Profile of Blood–Brain Barrier Remodeling in Cerebral Amyloid Angiopathy

RNA Profiling of Brain Microvessels Reveals Altered Morphology and Signaling in a Mouse Model of Alzheimer's Disease

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