Single-Cell Transcriptomic Profiling of subpopulations of vascular endothelial cells following acute lung injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE148499 | GEO | 2020/09/30
REPOSITORIES: GEO
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Project description:Single-Cell Transcriptomic Profiling of subpopulations of vascular endothelial cells following acute lung injury
| PRJNA624655 | ENA
Project description:Acute kidney injury (AKI) is a major health burden in the United States. Macrophages have been shown to mediate AKI in murine models. Murine kidneys contain multiple subpopulations of kidney resident macrophages (KRM) that are transcriptionally and spatially distinct. We hypothesized the human kidney contains orthologous KRM subpopulations, both transcriptionally and spatially. We utilized kidney sections from donors diagnosed with mild to moderate AKI in order to increase the translatability of murine research to clinical settings. We used spatial transcriptomics and single cell RNA sequencing to identify five distinct human KRM subpopulations. Using the AddModuleScore function in Seurat, we were able to compare the murine KRM transcriptional profiles from pre and post-AKI to the human KRM subpopulations. As a result, we identified four orthologous to known murine KRM subpopulations. The remaining population was identified in the kidney cortex and expresses a profile similar to activate microglia, the resident macrophage population in the brain. Again, we used AddModuleScore to determine a set of marker genes that will allow for the identification of KRM subsets across species and injury.
2024-03-01 | GSE226533 | GEO
Project description:Recovery of endothelial integrity after vascular injury is vital for endothelial barrier function and vascular homeostasis. However, little is known about the molecular mechanisms of endothelial barrier repair following injury. To investigate the functional role of forkhead box M1 (FoxM1) in the mechanism of endothelial repair, we generated endothelial cell-restricted FoxM1-deficient mice (FoxM1 CKO mice). These mutant mice were viable and exhibited no overt phenotype. However, in response to the inflammatory mediator LPS, FoxM1 CKO mice displayed significantly protracted increase in lung vascular permeability and markedly increased mortality. Following LPS-induced vascular injury, FoxM1 CKO lungs demonstrated impaired cell proliferation in association with sustained expression of p27(Kip1) and decreased expression of cyclin B1 and Cdc25C. Endothelial cells isolated from FoxM1 CKO lungs failed to proliferate, and siRNA-mediated suppression of FoxM1 expression in human endothelial cells resulted in defective cell cycle progression. Deletion of FoxM1 in endothelial cells induced decreased expression of cyclins, Cdc2, and Cdc25C, increased p27(Kip1) expression, and decreased Cdk activities. Thus, FoxM1 plays a critical role in the mechanism of the restoration of endothelial barrier function following vascular injury. These data suggest that impairment in FoxM1 activation may be an important determinant of the persistent vascular barrier leakiness and edema formation associated with inflammatory diseases.
| S-EPMC1555637 | biostudies-literature
Project description:Repair of the endothelial cell barrier after inflammatory injury is essential for tissue fluid homeostasis and normalizing leukocyte transmigration. However, the mechanisms of endothelial regeneration remain poorly understood. Here we show that the endothelial and hematopoietic developmental transcription factor Sox17 promotes endothelial regeneration in the endotoxemia model of endothelial injury. Genetic lineage tracing studies demonstrate that the native endothelium itself serves as the primary source of endothelial cells repopulating the vessel wall following injury. We identify Sox17 as a key regulator of endothelial cell regeneration using endothelial-specific deletion and overexpression of Sox17. Endotoxemia upregulates Hypoxia inducible factor 1?, which in turn transcriptionally activates Sox17 expression. We observe that Sox17 increases endothelial cell proliferation via upregulation of Cyclin E1. Furthermore, endothelial-specific upregulation of Sox17 in vivo enhances lung endothelial regeneration. We conclude that endotoxemia adaptively activates Sox17 expression to mediate Cyclin E1-dependent endothelial cell regeneration and restore vascular homeostasis.
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Project description:Alterations in the expression of the vascular endothelial growth factors (VEGF) A and B occur during blood⁻brain barrier (BBB) breakdown and angiogenesis following a brain injury. In this study, the temporal and spatial expression of VEGF-D and VEGF receptors-2 and -3 (VEGFR-2 and VEGFR-3, respectively) was determined at the mRNA and protein level in the rat cortical cold-injury model over a period of 0.5 to 6 days post-injury. In order to relate endothelial VEGF-D protein expression with BBB breakdown, dual labeling immunofluorescence was performed using antibodies to VEGF-D and to fibronectin, a marker of BBB breakdown. In control rats, VEGF-D signal was only observed in scattered perivascular macrophages in the cerebral cortex. The upregulation of VEGF-D mRNA expression was observed in the injury site between days 0.5 to 4, coinciding with the periods of BBB breakdown and angiogenesis. At the protein level, intracerebral vessels with BBB breakdown to fibronectin in the lesion on days 0.5 to 4 failed to show endothelial VEGF-D. Between days 0.5 to 6, increased VEGF-D immunoreactivity was noted in the endothelium of pial vessels overlying the lesion site, in neutrophils, macrophages, and free endothelial cells within the lesion. The upregulation of VEGFR-2 and -3 mRNA and protein expression was observed early post-injury on day 0.5. Although there was concurrent expression of VEGF-A, VEGF-B, and VEGF-D post-injury, differences in their spatial expression during BBB breakdown and angiogenesis suggest that they had specific and separate roles in these processes.
| S-EPMC6479775 | biostudies-literature
Project description:Sustained, indolent immune injury of the vasculature of a heart transplant limits long-term graft and recipient survival. This injury is mitigated by a poorly characterized, maladaptive repair response. Vascular endothelial cells respond to proangiogenic cues in the embryo by differentiation to specialized phenotypes, associated with expression of apelin. In the adult, the role of developmental proangiogenic cues in repair of the established vasculature is largely unknown. We found that human and minor histocompatibility-mismatched donor mouse heart allografts with alloimmune-mediated vasculopathy upregulated expression of apelin in arteries and myocardial microvessels. In vivo, loss of donor heart expression of apelin facilitated graft immune cell infiltration, blunted vascular repair, and worsened occlusive vasculopathy in mice. In vitro, an apelin receptor agonist analog elicited endothelial nitric oxide synthase activation to promote endothelial monolayer wound repair and reduce immune cell adhesion. Thus, apelin acted as an autocrine growth cue to sustain vascular repair and mitigate the effects of immune injury. Treatment with an apelin receptor agonist after vasculopathy was established markedly reduced progression of arterial occlusion in mice. Together, these initial data identify proangiogenic apelin as a key mediator of coronary vascular repair and a pharmacotherapeutic target for immune-mediated injury of the coronary vasculature.
| S-EPMC6934203 | biostudies-literature
Project description:The pituitary gland regulates growth, metabolism, reproduction, the stress response, uterine contractions, lactation, and water retention. It secretes polypeptide hormones in response to hypothalamic input, end organ feedback, and diurnal cues. The mechanisms by which pituitary stem cells are recruited to proliferate, maintain quiescence or differentiate into specific cell types, especially thyrotropes, are not well understood. We utilized single-cell RNA sequencing in juvenile P7 mouse pituitary cells to identify transcription factors in pituitary stem and endocrine populations, with a focus on thyrotrope subpopulations. We first identified common gene regulatory networks activated in proliferating stem and proliferating endocrine cells. We ascertained Shox2 and Sox14 as candidate regulators of pars distalis and pars tuberalis thyrotropes, respectively, and subsequently found reduced hormone expression in Sox14-knockout pars tuberalis thyrotropes. We further discovered dual-identity cells expressing both POU1F1 and NR5A1 and demonstrated that approximately one-third of pars distalis thyrotropes are descended from NR5A1-expressing cells, typically considered gonadotrope progenitors. We have therefore used single-cell transcriptomics to identify novel developmental mechanisms regulating the specification and hormone expression in thyrotrope subpopulations.
2022-09-02 | GSE205418 | GEO
Project description:Objective: This investigation examined the effect of velvet antler (VA) on endothelial progenitor cells (EPCs) and the associated effects to promote angiogenesis and repair vascular endothelial injury in rats with myocardial infarction (MI). Methods: VA was analyzed by liquid chromatography-mass spectrometry. Male Sprague Dawley rats were randomly divided into four groups: sham, MI, VA, and VA + DAPT (gamma-secretase inhibitor IX, a specific blocker of the Notch signaling pathway) group. The rats underwent ligation of the left anterior descending coronary artery for the establishment of MI. Sham-operated rats were used as controls. Blood was taken from the orbital plexus on the first and third days after the operation, and all rats were euthanized on the 7th day after surgery. The blood samples were used to detect the contents of circulating endothelial progenitor cells (CEPCs) and vascular endothelial growth factor (VEGF). Echocardiography was used to test the cardiac function. Cardiac tissue was used for immunohistochemistry and electron microscope, and the marginal zone of the MI tissue was used for western blot and reverse transcription-quantitative polymerase chain reaction. Results: The number of basically qualitative metabolites is 445. Among them, there are 74 substances with relative content greater than 0.05%. VA increased the concentration of CEPCs and VEGF in serum, CD133 content and microvessel density (MVD), and protected the morphology of microvascular endothelial cells in the marginal area of MI at 7 days post-MI surgery. CEPCs and MVD in the VA +DAPT group were lower than those of VA group. VA increased the protein expressions of Jagged-1, Notch1, NICD and HES1, and the mRNA expressions of Hes1 and Hey2, while some of the effects could be suppressed by DAPT. Conclusion: These results suggest that VA promotes the mobilization of EPCs to promote angiogenesis and repair vascular endothelial cell damage in post-MI rats, and these effects may be due to activation of the Notch signal pathway.
| S-EPMC6344410 | biostudies-literature
Project description:Exoenzyme Y (ExoY) is a Pseudomonas aeruginosa toxin that is introduced into host cells through the type 3 secretion system (T3SS). Once inside the host cell cytoplasm, ExoY generates cyclic nucleotides that cause tau phosphorylation and microtubule breakdown. Microtubule breakdown causes interendothelial cell gap formation and tissue edema. Although ExoY transiently induces interendothelial cell gap formation, it remains unclear whether ExoY prevents repair of the endothelial cell barrier. Here, we test the hypothesis that ExoY intoxication impairs recovery of the endothelial cell barrier following gap formation, decreasing migration, proliferation, and lung repair. Pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains for 6 h, including one possessing an active ExoY (PA103 exoUexoT::Tc pUCPexoY; ExoY(+)), one with an inactive ExoY (PA103?exoUexoT::Tc pUCPexoY(K81M); ExoY(K81M)), and one that lacks PcrV required for a functional T3SS (?PcrV). ExoY(+) induced interendothelial cell gaps, whereas ExoY(K81M) and ?PcrV did not promote gap formation. Following gap formation, bacteria were removed and endothelial cell repair was examined. PMVECs were unable to repair gaps even 3-5 days after infection. Serum-stimulated growth was greatly diminished following ExoY intoxication. Intratracheal inoculation of ExoY(+) and ExoY(K81M) caused severe pneumonia and acute lung injury. However, whereas the pulmonary endothelial cell barrier was functionally improved 1 wk following ExoY(K81M) infection, pulmonary endothelium was unable to restrict the hyperpermeability response to elevated hydrostatic pressure following ExoY(+) infection. In conclusion, ExoY is an edema factor that chronically impairs endothelial cell barrier integrity following lung injury.
| S-EPMC4025060 | biostudies-literature