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Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

ABSTRACT: Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

PROVIDER: PRJNA947622 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23942268_1.fastq.gz	Fastqsanger.gz
	SRR23942268_2.fastq.gz	Fastqsanger.gz
	SRR23942269_1.fastq.gz	Fastqsanger.gz
	SRR23942269_2.fastq.gz	Fastqsanger.gz
	SRR23942270_1.fastq.gz	Fastqsanger.gz

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Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

Project description:Neurodegenerative diseases (ND) are characterized by a progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent dendritic cells that drive formation of lesions. Some patients with systemic LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by hematopoietic cells that are clonal with systemic LCH lesion histiocytes. Strikingly, we discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enabling migration of into the brain where they differentiate into senescent, inflammatory macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs synergistically reduced parenchymal infiltration, neuroinflammation and neurologic damage in preclinical LCH-ND. MAPK activation in circulating myeloid cells represents a novel and targetable mechanism of ND.

2024-03-01 | GSE227984 | GEO

Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown

Project description:The blood brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory breakdown. Permeability of the BBB to polar molecules shows circadian variation due to rhythmic transporter expression, while basal permeability to polar molecules in non-rhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated lipopolysaccharide (LPS) injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions, then examined BBB permeability to a polar molecule. We observed clear diurnal variation in inflammatory BBB permeability, with a striking increase in BBB breakdown specifically following evening LPS injection. Evening LPS led to persisting glia activation and inflammation in the brain that was not observed in the periphery. The exaggerated evening neuroinflammation and BBB disruption were suppressed by microglial depletion, were associated with enhanced expression of the Nos2 gene, and could be prevented in vivo by treatment with an iNOS inhibitor. Our data show that diurnal rhythms in microglial inflammatory responses to LPS drive daily variability in BBB breakdown, and reveals time-of-day as a key regulator of inflammatory BBB disruption.

2024-12-06 | GSE263794 | GEO

Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown

Project description:Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown

| PRJNA1099251 | ENA

Vascular senescence and leak are features of the early breakdown of the blood-brain barrier in Alzheimer’s disease models.

Project description:Alzheimer’s disease (AD) is an age-related disease, with loss of integrity of the blood-brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Further, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB maybe valid therapeutic strategies.

2023-12-07 | GSE243576 | GEO

Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility

Project description:Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility

| PRJNA421967 | ENA

Single-cell census of the colonic epithelium reveals goblet cell drivers of barrier breakdown in inflammatory bowel disease

Project description:Colonic epithelial cells facilitate host-microbe interactions to control mucosal immunity, and they also coordinate recycling and forming the mucus barrier. Epithelial barrier breakdown underpins inflammatory bowel disease (IBD). However, we do not know the specific contributions of each epithelial cell subtype to this process. Here, we profiled single colonic epithelial cells in health and IBD. Our results identified previously unknown subtypes and crypt gradients of progenitors, colonocytes and goblet cells. We also revealed a novel specialized metal ion storage and chloride secretory cell. In IBD, we discovered a unique cluster of disease associated goblet cells that remodels the barrier. We found downregulated WFDC2, a novel goblet cell expressing anti-protease that inhibited bacterial growth. Our in vivo studies demonstrated WFDC2 preserved tight junction integrity and prevented commensal invasion and mucosal inflammation. We delineate markers and transcriptional states, identify a new colonic epithelial cell and uncover fundamental principles of epithelial plasticity and barrier breakdown in IBD. Thus, our study reveals new therapeutic targets and disease-related mechanisms in IBD

2019-02-16 | PXD011655 | Pride

Transcriptome analysis of senescent and reactive human fetal astrocytes

Project description:Senescence was recently linked to neurodegeneration. Senescent as well as reactive astrocytes were detected in Parkinson’s disease postmortem brains. This study aimed to determine differences and similarities between senescent and reactive astrocytes. Astrocytes were treated with the stressors hydrogen peroxide or rotenone to induce senescence or with the cytokines TNFa+IL1a or with IL1b to induce reactivity in astrocytes. Comparing the transcriptome of senescent and reactive astrocytes revealed a set of genes specific to senescent astrocytes together with genes regulated in a similar way in both astrocyte states.

2021-06-09 | GSE126750 | GEO

Colonic single epithelial cell census reveals goblet cell drivers of barrier breakdown in inflammatory bowel disease

Project description:Colonic single epithelial cell census reveals goblet cell drivers of barrier breakdown in inflammatory bowel disease

| PRJNA477814 | ENA

Transcriptome of senescent and non-senescent cells within PanIN pancreatic premalignant lesions in a KRas-driven mouse model

Project description:Cellular senescence is a central barrier to tumorigenesis, acting to block the proliferation of premalignant cells. However, senescent cells residing within tumor lesions can also exert paracrine effects influencing tumor growth and progression. Premalignant pancreatic intraepithelial neoplasia (PanIN) lesions contain senescent cells, yet whether these influence disease progression is unknown. Here we report that senescent cells in PanINs that develop in a Kras-driven mouse model express a pro-inflammatory gene signature, which includes high Cox2 levels. Pharmacologic Cox2 inhibition caused a dramatic reduction in PanIN growth. Senolytic treatment with the Bcl2-family inhibitor ABT-737 reduced the numbers of Cox2-expressing PanIN cells and blocked PanIN formation and progression to carcinoma. These findings indicate that senescent PanIN cells support tumor growth and progression through Cox2 activity, representing crosstalk between interspersed senescent and dividing premalignant cells. Targeted elimination of senescent cells may thus be effective in limiting progression of precancerous lesions.

2021-02-17 | GSE128319 | GEO

Genome-wide methylation maps for Proliferating and Senescent cells

Project description:Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence imposes a limit on proliferative potential that all cancer cells must bypass. Compared to proliferating cells, senescent cells exhibit marked chromatin re-organization. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread alterations in their DNA methylome. These changes are linked to mislocalization of the maintenance DNA methyltransferase (DNMT1) in cells approaching senescence, altered replication-coupled DNA methylation and de-repression of repetitive satellite sequences. Deficiency of DNMT1 triggers chromatin changes characteristic of senescence and expression of satellite sequences. Most importantly, but paradoxically, gains and losses of methylation in replicative senescence are similar to those in cancer, and this M-bM-^@M-^XreprogrammedM-bM-^@M-^Y methylation landscape is largely retained when cells escape or bypass senescence. In sum, altered regulation of DNMT1 in cells approaching replicative senescence contributes to changes in chromatin structure and function. Consequently, if senescent cells escape the proliferative barrier, they already harbor epigenetic changes likely to promote malignancy. Examination of methylation status in IMR90 cells

2013-11-25 | E-GEOD-48580 | biostudies-arrayexpress

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