Integrated single-cell multiomics reveals novel immune candidate markers for post-traumatic coagulopathy
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PROVIDER: PRJNA925472 | ENA |
REPOSITORIES: ENA
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Project description:Introduction: Post-traumatic coagulopathy (PTC) is a critical pathology in traumatic brain injury (TBI), however, its potential mechanism is not clear. To explore this in peripheral samples, we integrated single cell RNA-sequencing and T cell repertoire (TCR)-sequencing across a cohort of patients with TBI. Methods: Clinical samples from patients with more brain severity demonstrated altered mRNAs.
2023-02-02 | GSE223245 | GEO
Project description:IntroductionPost-traumatic coagulopathy (PTC) is a critical pathology in traumatic brain injury (TBI), however, its potential mechanism is not clear. To explore this in peripheral samples, we integrated single cell RNA-sequencing and T cell repertoire (TCR)-sequencing across a cohort of patients with TBI.MethodsClinical samples from patients with more brain severity demonstrated overexpression of T cell receptor-encoding genes and less TCR diversity.ResultsBy mapping TCR clonality, we found patients with PTC have less TCR clones, and the TCR clones are mainly distributed in cytotoxic effector CD8+T cell. In addition, the counts of CD8+ T cell and natural killer (NK) cells are associated with the coagulation parameter by WGCNA, and the granzyme and lectin-like receptor profiles are also decreased in the peripheral blood from TBI patients, suggesting that reduced peripheral CD8+ clonality and cytotoxic profiles may be involved in PTC after TBI.ConclusionOur work systematically revealed the critical immune status in PTC patients at the single-cell level.
| S-EPMC9946684 | biostudies-literature
Project description:Heat stroke is a life-threatening condition characterized by loss of thermoregulation and severe elevation of core body temperature, which can cause organ failure and damage to the central nervous system. While no definitive test exists to measure heat stroke severity, immune challenge is known to increase heat stroke risk, although the mechanism of this increased risk is unclear. In this study, we used a mouse model of classic heat stroke to test the effect of immune challenge on pathology. Employing multivariate supervised machine learning to identify patterns of molecular and cellular markers associated with heat stroke, we found that prior viral infection simulated with poly I:C injection resulted in heat stroke presenting with high levels of factors indicating coagulopathy. Despite a decreased number of platelets in the blood, platelets are large and non-uniform in size, suggesting younger, more active platelets. Levels of D-dimer and soluble thrombomodulin were increased in more severe heat stroke, and in cases presenting with the highest level of organ damage markers D-dimer levels dropped, indicating potential fibrinolysis-resistant thrombosis. Genes corresponding to immune response, coagulation, hypoxia, and vessel repair were up-regulated in kidneys of heat-challenged animals, and these increases correlated with both viral treatment and distal organ damage while appearing before discernible tissue damage to the kidney itself. We conclude that heat stroke-induced coagulopathy may be a driving mechanistic force in heat stroke pathology, especially when exacerbated by prior infection, and that coagulation markers may serve as an accessible biomarker for heat stroke severity and therapeutic strategies.
2020-05-15 | GSE129188 | GEO
Project description:Liver dysfunction including coagulopathy is a prominent feature of proteinenergy malnutrition. To identify mechanisms underlying malnutrition-associated coagulopathy, we administered low-protein low-fat diet to lactating dams and examined hepatic transcription and plasma coagulation parameters in young adult weanlings. Malnutrition impairs growth and liver synthetic function more severely in males versus females. Malnourished males are coagulopathic and exhibit decreased hepatocyte peroxisomes, FXR agonist bile acids, FXR binding on Fga and F11 gene regulatory elements, and coagulation factor synthesis. These effects are absent in female mice, which have low baseline levels of PPARα, suggesting that nutrient-sensing nuclear receptors regulate coagulation factor synthesis in response to host nutritional status in a sex-specific manner.
2020-10-27 | GSE156856 | GEO
Project description:Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s Disease (AD) and unaffected controls have been well-documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq + snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell-type specific transposase accessible regions that are enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglial links were globally enriched for heritability of AD risk and previously identified active regulatory regions.
2023-01-09 | GSE214637 | GEO
Project description:Malignant tumors trigger a complex network of inflammatory and wound repair responses, prompting Dvorak's characterization of tumors as 'wounds that never heal'. Some of these responses lead to profound defects in blood clotting, such as Disseminated Intravascular Coagulopathy (DIC), which correlate with poor prognoses. Here, we demonstrate that a new tumor model in Drosophila provokes phenotypes that recapitulate coagulopathies observed in patients. Fly ovarian tumors overproduce multiple secreted components of the clotting cascade and trigger hypercoagulation of fly blood (hemolymph). Hypercoagulation occurs shortly after tumor induction and is transient; it is followed by a hypocoagulative state such that tumor-bearing flies are defective in wound healing. Hypocoagulation is associated with exhaustion of host clotting components from the body, which is dependent on a tumor-produced clotting factor. Interestingly, clinical studies suggest that lethality in patients with high serum levels of clotting components can be independent of thrombotic events. We show that depleting tumor-produced clotting factors improves survival of tumor-bearing flies, despite the fact that flies have an open circulatory system. Our work establishes a platform for identifying alternative mechanisms by which tumor-driven coagulopathy triggers early mortality, as well as exploring other conserved mechanisms of host responses to chronic wounds.
2023-06-23 | GSE207849 | GEO
Project description:Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s Disease (AD) and unaffected controls have been well-documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq + snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell-type specific transposase accessible regions that are enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respe ctively. Microglial links were globally enriched for heritability of AD risk and previously identified active regulatory regions.
2023-01-09 | GSE214979 | GEO
Project description:Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s Disease (AD) and unaffected controls have been well-documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq + snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell-type specific transposase accessible regions that are enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglial links were globally enriched for heritability of AD risk and previously identified active regulatory regions.
2023-01-09 | GSE214911 | GEO
Project description:Trauma-induced coagulopathy (TIC) significantly contributes to trauma-related mortality, driven by dysregulated coagulation and fibrinolysis. Endotheliopathy of trauma (EoT) is central to TIC, yet its underlying mechanisms remain unclear. Current in vitro models fail to replicate the complex trauma environment, including haemorrhagic shock, tissue injury, and inflammation. This study aimed to develop a novel in vitro model of EoT that mimics key TIC features, enabling the investigation of endothelial contributions to TIC. Endothelial colony-forming cells (ECFCs) were exposed to trauma-relevant factors, including epinephrine, TNF-α, IL-6, HMGB1, hydrogen peroxide, and hypoxia. Endothelial injury markers (syndecan-1, thrombomodulin), haemostatic protein expression, coagulation, and fibrinolysis were analysed using ELISA, immunofluorescence, global haemostasis assays, and RNA sequencing. Plasma from healthy donors and trauma patients was used to assess clinical relevance. Traumatised ECFCs exhibited progressive dysfunction, with early surface damage and sustained fibrinolytic dysregulation. Transcriptomic analysis showed activation of inflammatory pathways, metabolic shifts, and epigenetic changes. Surface expression of anticoagulant proteins decreased, while procoagulant tissue factor increased, heightening thrombogenic potential. Initially, traumatised ECFCs promoted fibrinolysis via thrombomodulin shedding but later secreted antifibrinolytic PAI-1, mimicking the biphasic TIC phenotype. Plasma assays revealed thrombin generation and clot lysis changes similar to trauma patients. This in vitro model successfully replicates EoT and TIC-associated haemostatic imbalances, capturing the time-dependent evolution of endothelial dysfunction. It provides mechanistic insights into TIC and serves as a platform for testing targeted interventions to mitigate endothelial-driven coagulopathy in trauma.
2025-09-24 | GSE301085 | GEO
Project description:Identification of molecular markers for candidate sleep-promoting neurons in CeA using TRAP-seq
| PRJNA498969 | ENA