Effect of VEGF-C treatment on sorted meningeal CD45+ cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252093 | GEO | 2023/12/29
REPOSITORIES: GEO
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Project description:Transcriptional profiling of mouse dural lymphatic endothelial cells (LECs) in comparing AAV-Controls with AAV-VEGFC treaded mice. Objective was to determine the effect of the VEGFC treatment on global gene expression of LECs.
2023-12-29 | GSE252115 | GEO
Project description:Effect of VEGF-C treatment on sorted meningeal CD45+ cells
| PRJNA1057768 | ENA
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217312 | GEO
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217276 | GEO
Project description:The meninges, comprising the leptomeninges (pia and arachnoid layers) and the pachymeninx (dura layer), participate in CNS autoimmunity but their relative contributions remain unclear. Here, we report on findings in animal models of CNS autoimmunity and in multiple sclerosis patients, where, in chronic disease, the leptomeninges were highly inflamed and showed structural changes, while the dura mater was only marginally affected. Although dural vessels were leakier than leptomeningeal vessels, effector T cells adhered more weakly to the dural endothelium. Furthermore, local antigen presenting cells presented myelin and neuronal autoantigens less efficiently and the activation of autoreactive T cells was lower in dural than leptomeningeal layers, preventing local inflammatory processes. Direct antigen application was required to evoke a local inflammatory response in the dura. Together, our data demonstrate an uneven involvement of the meningeal layers in CNS autoimmunity, in which effector T cell trafficking and activation are functionally confined to the leptomeninges, while the dura remains largely shielded from CNS autoimmune processes.
2022-07-04 | GSE203046 | GEO
Project description:Purpose: The rediscovery of meningeal lymphatic vessels (MLVs) suggests a potential linkage between brain tumors and cervical lymph nodes (LNs). In this study, we investigated whether and how meningeal lymphatics regulate the metastasis of brain tumor cells. Experimental Design: We first examined the pattern of MLVs and LNs after tumor cells were injected into the cisterna magna (i.c.m.) or subdural space of mice. The meninges were isolated and analyzed by whole-mount immunofluorescence staining. LN metastasis was analyzed by detecting GFP+ tumor cells. Then we used inducible knock-out mice and AAV-VEGF-C delivery system to study the function of MLVs in mediating the metastasis of brain tumor cells. Finally, RNA-seq was used to determine the expression profiles of meningeal lymphatic endothelial cells (mLECs) in mice with or without tumors. The roles of the endothelial nitric oxide synthetase (eNOS) were evaluated both genetically and pharmacologically in vivo. Results: Meningeal lymphangiogenesis induced by GL261 and B16 tumors was correlated with dCLN swelling and metastasis. dCLN metastasis was suppressed in MLV-defective mice, while promoted in AAV-VEGF-C-treated mice. In addition, we found that VEGF-C/VEGFR3 signaling regulated both meningeal and tumor lymphangiogenesis. Tumor-associated mLECs have a distinct transcriptomic signature, which highly express eNOS. Furthermore, genetic or pharmacological inhibition of eNOS significantly suppressed meningeal lymphangiogenesis and dCLN metastasis. Conclusions: The meningeal lymphatic vasculature mediates the metastasis of brain tumors to cervical LNs, mainly through a VEGF-C/VEGFR3-eNOS signaling pathway, suggesting that MLV may be a potential therapeutic target for the extracranial metastasis of brain tumors.
2020-03-16 | GSE128207 | GEO
Project description:Exploration of proteome differences between CD45+ and CD45- cell types in renal cell carcinoma tumors and normal adjacent tissue patient samples.
2020-10-14 | PXD014370 | Pride
Project description:Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice. Intra-cerebrospinal administration of an adeno-associated virus expressing mouse full-length VEGF-C (AAV-mVEGF-C) increased CSF drainage to the deep cervical lymph nodes (dCLNs) by enhancing lymphatic growth, and upregulated neuroprotective signaling pathways identified by single nuclei RNA sequencing of brain cells. In a mouse model of ischemic stroke, AAV-mVEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage, associated with mitigated microglia-mediated inflammation and increased BDNF signaling in brain cells. Neuroprotective effects of VEGF-C were lost upon ligation of the dCLN afferent lymphatics, and not mimicked by acute post-stroke VEGF-C injection. We conclude that VEGF-C prophylaxis promotes multiple vascular, immune, and neural responses that culminate in a protection against neurological damage in acute ischemic stroke.
2024-02-27 | GSE252622 | GEO
Project description:The meningeal space is occupied by a diverse repertoire of innate and adaptive immune cells. CNS injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation in CNS injury remains poorly understood. Here we describe group 2 innate lymphoid cells (ILC2s) as a novel cell type resident in the healthy meninges that is activated following CNS injury. ILC2s are present throughout the naïve mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile relative to lung ILC2s. After spinal cord injury, meningeal ILC2s are activated in an IL-33 dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild type lung-derived ILC2s into the meningeal space of IL-33R-/- animals improves recovery following spinal cord injury. These data characterize ILC2s as a novel meningeal cell type that responds to and functionally affects outcome after spinal cord injury, and could lead to new therapeutic insights for CNS injury or other neuroinflammatory conditions.
2016-12-13 | GSE90908 | GEO
Project description:The meninges are a tripartite system of membranous tissue comprised of pial, arachnoid and dural layers that cover both the brain and spinal cord. Between the arachnoid and pial layers is the subarachnoid space filled with cerebrospinal fluid (CSF). Though the meninges have long been thought to provide largely a protective function, a growing number of studies highlight this tissue to be a nest of immune activity, harboring T cells, B cells, macrophages, and a variety of other myeloid cell types during health and disease. But despite the burgeoning prospect that the meninges might play a decidedly more active role in immune and other regulatory processes than previously thought, little is known about their structural makeup. Contributing to this void, considerable technical challenges prevent sophisticated analysis of the meninges at cellular and molecular levels. In addition, removal of the brain and spinal cord from their bony encasement leads to tearing of the tenuous meninges and significant disruption of the delicate inter-membrane arrangements. Also lacking are sufficient molecular targets to identify the various meningeal structural elements, only hinted at so far by scanning electron microscopy. Accordingly, we developed a method to allow removal of brain and spinal meninges while minimizing risk of parenchymal contamination and performed shotgun proteomics on the two meningeal domains. While the vast majority of proteins at both locales overlapped, several proteins – including those of structural nature – were exclusive to brain or spinal meninges. Targeting proteins revealed in the proteomic data, the cellular and extracellular elements that provide the meninges’ structure were identified using confocal and electron microscopy, and were observed for the first time in high-resolution
2023-11-01 | PXD039294 | Pride