Single-nucleus transcriptomics reveals sepsis-related neurovascular dysfunction in the human hippocampus
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PROVIDER: PRJNA1321899 | ENA |
REPOSITORIES: ENA
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Project description:Sepsis is increasingly recognized as a major precipitant of long-term cognitive impairment, yet the cellular mechanisms underlying hippocampal vulnerability remain elusive. Using single-nucleus RNA sequencing of human hippocampal tissues from sepsis and control patients, we identied profound neurovascular alterations involving 21 distinct cell populations. Notably, astrocytes and microglia exhibited marked polarization: Astrocyte 2 showed simultaneous upregulation of neurotoxic A1 and neuroprotective A2 gene signatures in sepsis, whereas Astrocyte 1 displayed reduced A1 activity and a relatively quiescent pro le. In parallel, Microglia 2 demonstrated a prominent M1-like in ammatory signature, including elevated expression of HLA-DRA, IL1B, and TNF, while Microglia 1 downregulated both M1 and M2 markers, suggesting a hypo-responsive state. Intercellular communication analysis revealed intensi ed astrocyte–microglia interactions in the septic hippocampus, potentially amplifying in ammatory signaling loops. Concurrently, endothelial and mural cells exhibited transcriptional signatures of blood-brain barrier (BBB) disruption, oxidative stress, and compromised vascular homeostasis. Key molecular pathways associated with antigen presentation, cytokine signaling, and vascular permeability were selectively activated across neurovascular compartments. Together, our ndings uncover a coordinated glial and vascular response to systemic in ammation, driven in part by dysfunctional astrocyte–microglia crosstalk and pro-in ammatory polarization. These changes may underlie BBB breakdown and contribute to sustained neuroin ammation and cognitive decline in sepsis survivors. Targeting glial-vascular signaling axes and modulating astrocyte or microglial polarization states may offer promising avenues for therapeutic intervention in post-sepsis neurological sequelae.
2025-09-11 | GSE307512 | GEO
Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis. For the RNA-Seq study reported here, 73 patients were recruited with deferred consent at the time of first examination in an emergency ward based on the opinion of physicians that there was a potential for the patient's condition to develop into sepsis. These were retrospectively divided into groups based on clinical features and compared to 11 non-urgent surgical controls.
2014-11-14 | E-GEOD-63311 | biostudies-arrayexpress
Project description:Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood–brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
2022-06-03 | GSE163122 | GEO
Project description:Arterial hypertension is a leading cause of cognitive impairment, attributed to hemodynamic insufficiency, blood-brain barrier disruption, and white matter damage. However, the molecular mechanisms by which hypertension affects brain cells remain unclear. Using scRNA-seq in a mouse model of hypertension induced by angiotensin II, we mapped neocortical transcriptomic changes before (3 days) and after (42 days) onset of neurovascular and cognitive deficits. Surprisingly, evidence of endothelial transport disruption and senescence, stalled oligodendrocyte differentiation, interneuronal hypofunction and network imbalance emerged after just 3 days. By 42 days, when cognitive impairment becomes apparent, deficits in myelination and axonal conduction, as well as neuronal mitochondrial dysfunction, developed. These findings reveal a previously unrecognized early vulnerability of endothelial cells, interneurons, and oligodendrocytes, and provide the molecular bases for the subsequent neurovascular dysfunction and cognitive impairment in hypertension. In addition, the data constitute a valuable resource for future mechanistic studies and therapeutic target validation.
2025-04-17 | GSE294795 | GEO
Project description:Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA-sequencing of human cerebral cortex
| PRJNA684945 | ENA
Project description:Hepatic PPARα dysfunction in porcine sepsis
| PRJNA904738 | ENA
Project description:Obesity is a global pandemic and a key risk factor for several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease, or dementia. The neurovascular unit (NVU), essential for blood-brain barrier (BBB) integrity and comprised of endothelial cells, glial cells (microglia and astrocytes), and neurons, plays an important role in the pathogenesis of neurodegenerative diseases. However, molecular mechanisms underlying the effects of obesity on endothelial and other cells of and its contribution to neurodegeneration remains largely unknown, especially in females. In this study we aimed to decipher in-dept molecular modifications induced by obesity in cells of neurovascular unit by integrative multiomics analysis of endothelial cells, neurons, microglial cells, and astrocytes from the hippocampus of ob/ob female mice. Hippocampus were isolated from ob/ob and C57BL/6J female mice at 17-18 weeks of age. Gene expression profiles of cells of hippocampus were obtained using single nuclei RNA sequencing (snRNAseq) and data analyzed using in-depth bioinformatic analyses.
2025-10-01 | GSE263863 | GEO
Project description:Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Clinical trials in sepsis have mainly focused on targeting the inflammatory pathway, however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities to treat human sepsis patients. The role of PPARα in liver dysfunction during sepsis has recently been described, and restoring PPARα signaling proves to be successful in murine sepsis. To find out whether this therapy might also be helpful in human sepsis patients, we analyzed metabolic perturbations in liver of a porcine fecal peritonitis model. Resuscitation with fluids, antimicrobial therapy and abdominal drainage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected problems with PPARα signaling in the livers of septic pigs and reduced PPARα levels correlated well with disease severity. As PPARα regulates the expression of many genes involved in FA oxidation, reduced expression of these target genes concomitant with increased FFAs in plasma and ectopic lipid deposition in the liver was observed. The results obtained in pigs are in agreement with earlier observations in mice and support the potential of targeting defective PPARα signaling in the clinic.
2022-11-28 | GSE218636 | GEO
Project description:Hypertension-Induced Neurovascular and Cognitive Dysfunction at Single-Cell Resolution
| PRJNA1251611 | ENA
Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis.
2014-11-14 | GSE63311 | GEO