Single cell transcriptomic analyses of the developing meninges reveal meningeal fibroblast diversity and function
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ABSTRACT:
PROVIDER: PRJNA631534 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11746778_1.fastq.gz | Fastqsanger.gz | |||
| SRR11746778_2.fastq.gz | Fastqsanger.gz | |||
| SRR11746779_1.fastq.gz | Fastqsanger.gz | |||
| SRR11746779_2.fastq.gz | Fastqsanger.gz | |||
| SRR11746780_1.fastq.gz | Fastqsanger.gz |
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Project description:The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid and pial. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial sub-population marked by expression of µ-Crystallin. Developmental analysis reveals a progressive, ventral to dorsal maturation of telencephalic meninges. Our studies present an unprecedented view of meningeal fibroblasts, providing a molecular profile of embryonic meningeal fibroblasts by layer that yield insights into mechanisms of meninges development and function.
2020-07-06 | GSE150219 | GEO
Project description:The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single-cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid, and pia. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial subpopulation marked by the expression of μ-crystallin. Developmental analysis reveals a progressive, ventral-to-dorsal maturation of telencephalic meninges. Our studies have generated an unparalleled view of meningeal fibroblasts, providing molecular profiles of embryonic meningeal fibroblasts by layer and yielding insights into the mechanisms of meninges development and function.
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Project description:In this work we report that early developing B cells present in the meninges of mice at all ages. Single cell RNA-sequencing (scRNA-seq) analysis revealed a consecutive trajectory of meningeal developing B cells in mice and non-human primates (NHPs). Parabiosis together with lineage tracing of hematopoietic stem cells (HSCs) showed that meningeal developing B cells are continuously replenished from the HSC-derived progenitors via a circulation-independent route. Importantly, autoreactive immature B cells which recognize myelin oligodendrocyte glycoprotein (MOG), a central nervous system (CNS)-specific antigen, are eliminated from the meninges but not BM. Furthermore, genetic deletion of MOG tolerated the development/presence/residence of self-reactive B cells in the meninges. Thus, we propose that meninges function as a unique reservoir for B cell development, allowing in situ negative selection of CNS-antigen-autoreactive B cell clones to ensure a local non-self-reactive immune repertoire.
2021-11-01 | GSE176263 | GEO
Project description:Postnatal brain neurogenesis in mammals is believed to be restricted to rare germinative remnants of the neuroepithelium. In this study, we discovered that, in the postnatal brain, a subset of embryonically derived progenitors is present in meningeal substructures. These cells migrate from the meningeal substructures to the retrosplenial and visual motor cortex and differentiate into (electrically) functional integrated neurons. Lineage tracing analysis revealed that this subset of neural progenitors originate largely from PDGFR+ cells. PDGFR-derived cells differentiate mostly into Satb2+ neurons in cortical layers I-IV. Thus, a reservoir of embryonically derived progenitors in the meninges contributes to postnatal cerebral cortical neurogenesis.
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Project description:The meninges are important for brain development and pathology. Using single-cell RNA-sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared to their adult counterparts. We also identified novel meningeal microglia-like populations that appear to participate in white matter development. Early after hypoxic-ischemic insult, neutrophil numbers increased and they exhibited increased granulopoiesis, suggesting that the meninges are an important site of immune cell expansion with implications for the initiation of inflammatory cascades after neonatal brain injury. Our study provides a single-cell-resolution view of the importance of meningeal leukocytes at different stages of development in health and disease. DOI:10.1101/gad.348190.120
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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
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Project description:The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. How pain and neuro-immune interactions impact meningeal host defenses is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over one million people a year. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and may be a potential treatment for bacterial meningitis.
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Project description:Ectopic lymphoid tissue containing B cells forms in the meninges at late stages of human multiple sclerosis (MS) and when neuroinflammation is induced by interleukin (IL)-17 producing T helper (Th17) cells in rodents. B cell differentiation and the subsequent release of class-switched immunoglobulins have been speculated to occur in the meninges, but the exact cellular composition and underlying mechanisms of meningeal-dominated inflammation remain unknown. Here, we performed in depth characterization of meningeal vs. parenchymal Th17-induced rodent neuroinflammation. The most pronounced cellular and transcriptional differences between these compartments was the localization of B cells exhibiting a follicular phenotype exclusively to the meninges. Correspondingly, meningeal but not parenchymal Th17 cells, acquired a B cell-supporting phenotype and resided in close contact with B cells. This preferential B cell tropism for the meninges and the formation of meningeal ectopic lymphoid tissue was partially dependent on the expression of the transcription factor Bcl6 in Th17 cells, that is required in other T cell lineages to induce isotype class-switching in B cells. A function of Bcl6 in Th17 cells was only detected in vivo and was reflected by the induction of B cell-supporting cytokines, the appearance of follicular B cells in the meninges, and of immunoglobulin class-switching in the CSF. We, thus, identify the induction of a B cell-supporting meningeal microenvironment by Bcl6 in Th17 cells as a novel mechanism controlling compartment-specificity in neuroinflammation.
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Project description:The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single cell analyses, confocal 35 imaging, bone marrow chimeras and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvaria- meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that 40 populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells which may help maintain immune privilege within the CNS.
2021-06-01 | GSE174834 | GEO
Project description:The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single cell analyses, confocal 35 imaging, bone marrow chimeras and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvaria- meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that 40 populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells which may help maintain immune privilege within the CNS.
2021-06-01 | GSE174835 | GEO