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Cited by 123Barrier Structure and Function StudiesCerebrospinal fluid and hydrocephalusNeuroinflammation and Neurodegeneration Mechanisms

Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease

Open access
Derk, Julia, Jones, Hannah E., Como, Christina, Pawlikowski, Bradley, Siegenthaler, Julie A.·2021·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2021.703944PMC PMC8281977
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Abstract

The meninges are the fibrous covering of the central nervous system (CNS) which contain vastly heterogeneous cell types within its three layers (dura, arachnoid, and pia). The dural compartment of the meninges, closest to the skull, is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, as well as immune cells which are distinct from the CNS. Segregating the outer and inner meningeal compartments is the epithelial-like arachnoid barrier cells, connected by tight and adherens junctions, which regulate the movement of pathogens, molecules, and cells into and out of the cerebral spinal fluid (CSF) and brain parenchyma. Most proximate to the brain is the collagen and basement membrane-rich pia matter that abuts the glial limitans and has recently be shown to have regional heterogeneity within the developing mouse brain. While the meninges were historically seen as a purely structural support for the CNS and protection from trauma, the emerging view of the meninges is as an essential interface between the CNS and the periphery, critical to brain development, required for brain homeostasis, and involved in a variety of diseases. In this review, we will summarize what is known regarding the development, specification, and maturation of the meninges during homeostatic conditions and discuss the rapidly emerging evidence that specific meningeal cell compartments play differential and important roles in the pathophysiology of a myriad of diseases including: multiple sclerosis, dementia, stroke, viral/bacterial meningitis, traumatic brain injury, and cancer. We will conclude with a list of major questions and mechanisms that remain unknown, the study of which represent new, future directions for the field of meninges biology.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the cellular diversity of the meninges—dura, arachnoid, and pia—and argues that meningeal fibroblasts, barrier cells, vasculature, lymphatics, and immune cells are active interfaces between the CNS and periphery in development, homeostasis, injury, and disease. It highlights emerging roles in multiple sclerosis, Alzheimer’s disease, stroke/TBI, meningitis, and cancer, and lists major open questions.

Key findings

  • Meningeal fibroblasts are molecularly distinct by layer: pial fibroblasts are enriched in ECM genes, arachnoid fibroblasts express RALDH2 and CRABP2 and produce retinoic acid that regulates brain/neurovascular development, and dural fibroblasts include periosteal and dural border populations. The primary meninx appears by E10.5 in mouse, layers are identifiable by E13.5 in ventral forebrain, and arachnoid barrier cells are first seen around E13; perivascular fibroblasts can extend over 200 μm on cerebral penetrating arterioles but only short distances on ascending venules.
  • The arachnoid barrier is epithelial-like, with tight junctions (Claudin 11) and E-cadherin, and is enriched in transporters including ABCB1/Pgp, ABCG2/BCRP, ABCC4, OAT1, and OAT3. Pial vessels are barrier-like, lack PLVAP, express GLUT-1, and are impermeable to 44 kD horseradish peroxidase, whereas dural vessels are fenestrated and permeable to 44 kD HRP; dural lymphatics develop postnatally and become fully functional by approximately postnatal day 20 in mouse, draining CNS content to cervical lymph nodes.
  • Leptomeninges primarily harbor macrophages and non-migratory dendritic cells, while dura contains macrophages, mast cells, B cells, T cells, neutrophils, innate lymphoid cells, and the largest CNS dendritic cell population. Border-associated macrophages originate from yolk sac erythro-myeloid progenitors; leptomeningeal BAMs express CD206 and Lyve1 and are long-lived, whereas dural BAMs lack Lyve1 and are continuously renewed by peripheral monocytes.
  • In disease, meningeal and perivascular fibroblasts drive fibrotic scar formation after acute CNS injury; in EAE/MS, fibroblast expansion is deleterious for oligodendrocyte precursor cell differentiation and migration; meningeal lymphatic dysfunction is implicated in Alzheimer’s disease and TBI; meningitis involves immune infiltration and barrier disruption; and the leptomeninges are a common site for cancer metastasis.

Methods

  • Narrative review; no primary data are reported.
  • It synthesizes published literature on meningeal development, homeostasis, injury, and disease, with figures and a table of future directions.
  • Main analysis is thematic synthesis across meningeal cell types and disease contexts; no systematic search or meta-analysis is described.

Limitations

  • Stated: many unknowns and future directions are listed, including whether embryonic regionalization persists in adult meninges, layer-specific meningeal functions, arachnoid barrier development/function and leakiness, dural vasculature development, and CNS fibroblast identity/nomenclature.
  • Stated: there is a lack of consensus on fibrotic scar cell nomenclature, with cells called stromal cells, mesenchymal cells, Type A pericytes, Type 2 pericytes, and fibroblasts.
  • Evident: as a narrative review, it does not report primary experimental results, systematic search criteria, or quantitative synthesis; conclusions depend on the cited literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fncel.2021.703944

Cites

205 of 205 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 111 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Arachnoid fibroblasts express RALDH2 and CRABP2, a retinoic acid (RA) synthesizing enzyme and an RA binding protein, respectively.

    “Arachnoid fibroblasts express RALDH2 and CRABP2, a retinoic acid (RA) synthesizing enzyme and an RA binding protein, respectively (Figures 1D,E; DeSisto et al., 2020).”
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    • cites DeSisto et al., 2020 source

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  • Premisecitation

    Disruption of glymphatic function results in lower levels of TBI-associated biomarkers in the cervical lymph nodes and bloodstream.

    “disruption of glymphatic function results in lower levels of TBI-associated biomarkers in the cervical lymph nodes and bloodstream”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Plog et al., 2015 source

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  • Premisecitation

    Production of RA by the arachnoid layers critically regulates brain and neurovascular development.

    “Production of RA by the arachnoid layers critically regulates brain and neurovascular development (Siegenthaler et al., 2009; Choi et al., 2014; Bonney et al., 2016; Mishra et al., 2016; Haushalter et al., 2017).”
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    • cites Siegenthaler et al., 2009 source

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    • cites Choi et al., 2014 source

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    • cites Bonney et al., 2016 source

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  • Premisecitation

    Meningeal immune cells play an important role in the brain injury response.

    “numerous studies show that meningeal immune cells play an important role in the brain injury response”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Arac et al., 2014 source

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    • cites Corps et al., 2015 source

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    • cites Iadecola et al., 2020 source

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    • Rests on an assumption: The degree of neuroinflammation following acute CNS injury is a major predictor of clinical outcomes.
  • Interpretationcitation

    Resident meningeal macrophages regulate the acute injury response by influencing the severity of neuroinflammation and fibrosis.

    “Resident meningeal macrophages regulate the acute injury response by influencing the severity of neuroinflammation and fibrosis”
    Quote in the paperSubstantial claim
  • May combine two claims. 49
  • Classified as probably not a substantial claim. 2
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    Findingcitation

    Our recent scRNAseq of developing mouse meninges showed pia, arachnoid and dura fibroblasts are molecularly distinct and likely have layer specific functions.

    “Our recent single cell RNA sequencing (scRNAseq) of developing mouse meninges showed pia, arachnoid and dura fibroblasts are molecularly distinct and likely have layer specific functions (DeSisto et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites DeSisto et al., 2020 source

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    Findingcitation

    Arachnoid barrier cells can be first seen in the mouse forebrain around E13 and they differentiate from mesenchymal cells of the primary meninx.

    “We recently found that arachnoid barrier cells can be first seen in the mouse forebrain around E13 and they differentiate from mesenchymal cells of the primary meninx (DeSisto et al., 2020).”
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    • cites DeSisto et al., 2020 source

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    Premisecitation

    Meningeal fibroblasts in different CNS regions have different origins; forebrain meningeal fibroblasts are neural crest derived whereas mid-, hindbrain and spinal cord meninges are derived from the mesoderm.

    “Meningeal fibroblasts in different CNS regions have different origins; forebrain meningeal fibroblasts are neural crest derived whereas mid-, hindbrain and spinal cord meninges are derived from the mesoderm (Jiang et al., 2002; Yoshida et al., 2008).”
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    • cites Jiang et al., 2002 source

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    • cites Yoshida et al., 2008 source

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    Premisecitation

    The dural compartment of the meninges is closest to the skull and is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, and immune cells distinct from the CNS.

    “The dural compartment of the meninges, closest to the skull, is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, as well as immune cells which are distinct from the CNS.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Shukla et al., 2002, 2003

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    • cites Louveau et al., 2015 source

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    • cites Mrdjen et al., 2018 source

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    Premisecitation

    In a mild closed-skull compression injury model, Cx3cr1+ meningeal macrophages die within 30 min of injury induction, leading to formation of a honeycomb network of microglia at the glial limitans that likely prevents the spread of reactive oxygen species from the leptomeninges into the brain parenchyma.

    “Cx3cr1+ meningeal macrophages are observed dying within 30 min of injury induction, leading to formation of a “honeycomb” network of microglia at the glial limitans, likely preventing the spread of reactive oxygen species from the leptomeninges into the brain parenchyma”
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    • cites Roth et al., 2013 source

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    Interpretationreasoning

    Fibroblast production of retinoic acid impairs CNS recovery while stimulating fibrosis.

    “Thus, fibroblast production of retinoic acid seems to impair CNS recovery while stimulating fibrosis.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In both MCAO and SCI models, macrophages are observed in the fibrotic scar and may associate with fibroblasts, and CD11b+ macrophages are partially responsible for recruitment of fibroblasts to the fibrotic scar following SCI.

    “In both MCAO and SCI models, macrophages are observed in the fibrotic scar and may associate with fibroblasts”
    • Also stated in: § Meningeal Immune Cells in Acute CNS Injury · plain
      “CD11b+ macrophages are partially responsible for recruitment of fibroblasts to the fibrotic scar following SCI”
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    • cites Zhu et al., 2015 source

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    • cites Kelly et al., 2016 source

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  • May combine two claims.

    Interpretationnone given

    The emerging view of the meninges is as an essential interface between the CNS and the periphery, critical to brain development, required for brain homeostasis, and involved in a variety of diseases.

    “While the meninges were historically seen as a purely structural support for the CNS and protection from trauma, the emerging view of the meninges is as an essential interface between the CNS and the periphery, critical to brain development, required for brain homeostasis, and involved in a variety of diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The pial vasculature has barrier properties and is part of the meninges blood-CSF barrier.

    “Several studies show this vasculature has barrier properties and are therefore part of the meninges blood-CSF barrier.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Nabeshima et al., 1975 source

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    • cites Balin et al., 1986 source

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    • cites Butt et al., 1990 source

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  • May combine two claims.

    Interpretationreasoning

    The glymphatic system functions in clearance of molecular substances from the brain and potentially facilitates signaling between the brain and periphery.

    “These results highlight the important function of the glymphatic system in clearance of molecular substances from the brain and potential role in facilitating signaling between the brain and periphery.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Retinoic acid treatment following stroke in rodents reduces neurogenesis, angiogenesis, and gliogenesis in the peri-infarct region.

    “retinoic acid treatment following stroke in rodents reduces neurogenesis while also reducing angiogenesis and gliogenesis in the peri-infarct region”
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    • cites Jung et al., 2007 source

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    Premisecitation

    The pia is collagen and basement membrane-rich, abuts the glial limitans, and has regional heterogeneity within the developing mouse brain.

    “Most proximate to the brain is the collagen and basement membrane-rich pia matter that abuts the glial limitans and has recently be shown to have regional heterogeneity within the developing mouse brain.”
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    • cites DeSisto et al., 2020 source

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    Premisecitation

    Following TBI, glymphatic fluid flow is disrupted and greater amounts of tau protein accumulate in the parenchyma, and knock-out of Aqp4 exacerbates tau accumulation.

    “Following TBI, glymphatic fluid flow is disrupted and greater amounts of tau protein is observed accumulating in the parenchyma”
    • Also stated in: § Meningeal Lymphatics in Acute CNS Injury · plain
      “knock-out of Aqp4, a water transport channel necessary for interstitial solute clearance and glymphatic function, following TBI, exacerbates the accumulation of tau in the parenchyma”
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    • cites Iliff et al., 2014 source

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    Premisecitation

    Depletion of meninges-located mast cells in stroke pathology results in decreased neuroinflammation, brain swelling, and infarct size following stroke, partially mediated by mast-cell derived IL-6.

    “depletion of mast cells resulted in decreased levels of neuroinflammation, brain swelling, and infarct size following stroke and this was partially mediated by mast-cell derived IL-6”
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    • cites Arac et al., 2019 source

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    Premisecitation

    Lymphangiogenesis was seen following photothrombotic stroke lesion in the mouse cortex, but this effect was not seen following MCAO.

    “lymphangiogenesis was seen following photothrombotic stroke lesion in the mouse cortex, but this effect was not seen following MCAO”
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    • cites Yanev et al., 2020 source

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    Premisecitation

    In a sub-arachnoid hemorrhage model, depletion of macrophages in the leptomeninges and perivascular spaces surrounding large arterioles prior to injury results in improved neurological scoring and reduced inflammation and neuronal cell death.

    “depletion of macrophages in the leptomeninges and perivascular spaces surrounding large arterioles prior to injury results in improved neurological scoring and reduced levels of inflammation and neuronal cell death”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wan et al., 2021 source

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    Premisecitation

    In a mild closed-skull TBI model, meningeal lymphatic drainage is impaired likely due to increases in intracranial pressure, accompanied by lymphatic morphological changes, and lymphangiogenesis was observed up to 2 weeks following TBI without increased lymphatic function.

    “In a mild closed-skull TBI model, meningeal lymphatic drainage is impaired likely due to increases in intracranial pressure, accompanied by lymphatic morphological changes”
    • Also stated in: § Meningeal Lymphatics in Acute CNS Injury · plain
      “lymphangiogenesis was observed up to 2 weeks following TBI, though this did not correspond with increased lymphatic function”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bolte et al., 2020 source

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  • May combine two claims.

    Interpretationcitation

    The dural lymphatic function is disrupted following acute CNS injury, with impairment dependent on injury mechanism.

    “The dural lymphatic function is also disrupted following acute CNS injury.”
    • Also stated in: § Meningeal Lymphatics in Acute CNS Injury · plain
      “Thus, the degree of lymphatic impairment and response is dependent on the injury mechanism”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BBB breakdown is a well-documented feature of MS and there is some evidence that MS can also induce disruption of the arachnoid barrier in the meninges, part of the B-CSF barrier, with Claudin 11 downregulated in late stages of an EAE mouse model.

    “BBB breakdown is a well-documented feature of MS”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · hedged
      “there is some evidence that MS can also induce disruption of the arachnoid barrier in the meninges, part of the B-CSF barrier”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · plain
      “Claudin 11 is a tight junction protein enriched in arachnoid barrier cells and it is downregulated in late stages of an EAE mouse model”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Russi and Brown, 2015

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    • cites Uchida et al., 2019b

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    Premisecitation

    The leptomeninges are a key player in multiple sclerosis (MS), and in both MS patients and MS mouse models, immune cells infiltrate the leptomeninges and pathology is commonly seen in cortical areas adjacent to the meninges.

    “The leptomeninges are now recognized as a key player in multiple sclerosis (MS), an inflammatory CNS autoimmune disorder characterized by axon demyelination”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · plain
      “In both MS patients and MS mouse models, immune cells infiltrate the leptomeninges and pathology is commonly seen in cortical areas adjacent to the meninges”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Russi and Brown, 2015

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    • cites Lucchinetti et al., 2011 source

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  • May combine two claims.

    Interpretationreasoning

    A disruption to the arachnoid barrier could permit dural and peripheral immune cells to migrate into the leptomeninges, and potentially contribute to leptomeningeal immune infiltrate that is common in MS pathology.

    “A disruption to the arachnoid barrier could permit dural and peripheral immune cells to migrate into the leptomeninges, and potentially contribute to leptomeningeal immune infiltrate that is common in MS pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cytokine administration into the cisterna magna of mice is sufficient to drive arachnoid barrier and blood-cerebral spinal fluid barrier functional breakdown, and activated T cells in the leptomeninges produce cytokines known to perturb tight junction integrity of brain endothelial cells, including IFNγ which is known to drive BBB breakdown in viral encephalitis.

    “cytokine administration into the cisterna magna of mice is sufficient to drive arachnoid barrier and blood-cerebral spinal fluid barrier functional breakdown”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · boosted
      “Activated T cells in the leptomeninges produce cytokines known to perturb tight junction integrity of brain endothelial cells, including IFNγ which is known to drive BBB breakdown in viral encephalitis”
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    • cites Ichikawa and Itoh, 2011

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    • cites Bonney et al., 2019 source

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  • May combine two claims.

    Premisecitation

    In the EAE mouse model of MS, autoreactive effector T cells first infiltrate the leptomeninges via the pial vasculature, are activated by antigen presenting meningeal/perivascular macrophages, and subsequently enter the CNS parenchyma, triggering lesion formation.

    “In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, autoreactive effector T cells first infiltrate the leptomeninges via the pial vasculature, are activated by antigen presenting meningeal/perivascular macrophages, and subsequently enter the CNS parenchyma, triggering lesion formation”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bartholomäus et al., 2009 source

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    • cites Schläger et al., 2016 source

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  • May combine two claims.

    Premisecitation

    In cases of bacterial meningitis, infections usually start as skin, gastrointestinal or respiratory infections that spread to the blood, and bacteria accumulate in the leptomeningeal vasculature and move into the meninges by inducing BBB breakdown.

    “In cases of bacterial meningitis, infections usually start as skin, gastrointestinal or respiratory infections that spread to the blood”
    • Also stated in: § Response of the Meninges to Meningitis · plain
      “Once in the blood, the meningitis causing bacteria accumulate in the leptomeningeal vasculature”
    • Also stated in: § Response of the Meninges to Meningitis · plain
      “move into the meninges by inducing BBB breakdown through multiple mechanisms”
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    • cites Doran et al., 2016 source

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    • cites Mook-Kanamori et al., 2011 source

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    • cites van Sorge and Doran, 2012

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    Premisecitation

    Pre-existing defects in meningeal lymphatics cause worsened neuroinflammation following TBI, and stimulating meningeal lymphatic vessel outgrowth via VEGF-C administration had decreased levels of gliosis.

    “pre-existing defects in meningeal lymphatics causes worsened neuroinflammation following TBI”
    • Also stated in: § Meningeal Lymphatics in Acute CNS Injury · plain
      “stimulating meningeal lymphatic vessel outgrowth via VEGF-C administration had decreased levels of gliosis”
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    • cites Bolte et al., 2020 source

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    Premisecitation

    Blockage of VEGFR3 in mice following focal cerebral ischemia resulted in reduced inflammatory response and infarct, while VEGFR3 mutant mice subjected to MCAO develop larger stroke volumes and worsened edema.

    “Blockage of VEGFR3 (expressed by lymphatic endothelial cells) in mice following focal cerebral ischemia resulted in reduced inflammatory response and infarct”
    • Also stated in: § Meningeal Lymphatics in Acute CNS Injury · plain
      “VEGFR3 mutant mice subjected to MCAO develop larger stroke volumes, thus worsened edema”
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    • cites Esposito et al., 2019 source

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    • cites Yanev et al., 2020 source

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    Premisecitation

    In the LCMV Armstrong mouse model, recruitment of antiviral CD8+ T cells is necessary to defeat the infection but can also be deleterious, as CD8+ T cells produce cytokines that lead to over infiltration of monocytes and neutrophils that drive breakdown of vascular integrity and induce severe edema and brainstem herniation.

    “In the LCMV Armstrong mouse model, it was shown that the recruitment of antiviral CD8+ T cells, while necessary to defeat the infection, can also be deleterious.”
    • Also stated in: § Response of the Meninges to Meningitis · hedged
      “These CD8+ T cells also produce cytokines that can lead to over infiltration of monocytes and neutrophils that drive breakdown of vascular integrity and induce severe edema and brainstem herniation”
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    • cites Kim et al., 2009 source

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    • cites Mastorakos and McGavern, 2019

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AD is a dementia inducing neurodegenerative disorder characterized by the accumulation of amyloid-β containing plaques, which were initially isolated from homogenates of AD patient meningeal tissue.

    “AD is a dementia inducing neurodegenerative disorder characterized by the accumulation of amyloid-β containing plaques, which were initially isolated from homogenates of AD patient meningeal tissue”
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    • cites Joachim et al., 1988 source

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    • cites Da Mesquita et al., 2018b

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  • May combine two claims.

    Premisecitation

    The presentation of MS induced leptomeningeal inflammation can be variable, ranging from disorganized collections of immune cells to organized ectopic lymphoid follicle-like structures, and these ectopic lymph structures are potentiated by leptomeningeal fibroblasts which form a reticular cell network consisting of activated fibroblasts in a scaffold-like structure that might be driven by a subset

    “The presentation of MS induced leptomeningeal inflammation can be variable, ranging from disorganized collections of immune cells to organized ectopic lymphoid follicle-like structures”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · plain
      “the ectopic lymph structures seen in MS are potentiated by leptomeningeal fibroblasts which form a reticular cell network consisting of activated fibroblasts in a scaffold-like structure”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Choi et al., 2012 source

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    • cites Pikor et al., 2015 source

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    • cites Pikor et al., 2017 source

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    Premisecitation

    Increased number of PDGFRβ-expressing cells are detected in human MS pathology samples and increased ECM protein deposition is a common pathological feature of MS lesions.

    “Increased number of PDGFRβ-expressing cells are detected in human MS pathology samples”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · plain
      “increased ECM protein deposition is a common pathological feature of MS lesions”
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    • cites Dias et al., 2020 source

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    • cites van Horssen et al., 2006 source

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  • May combine two claims.

    Premisecitation

    Both the brain glymphatic and meningeal lymphatic systems deteriorate with age and their dysfunction can potentiate AD pathology and dementia.

    “both the brain glymphatic and meningeal lymphatic systems deteriorate with age”
    • Also stated in: § The Meninges and Alzheimer’s Disease · plain
      “their dysfunction can potentiate AD pathology and dementia”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kress et al., 2014 source

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    • cites Da Mesquita et al., 2018a

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    • cites Peng et al., 2016 source

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  • May combine two claims.

    Premisecitation

    A scRNAseq analysis showed that fibroblasts from EAE lesions upregulate interferon γ (IFNγ) signaling, and conditional deletion of IFN receptor γ from fibroblasts partially blocked fibroblast expansion, and IFNγ is produced by spinal cord T cells in EAE mice, implicating immune cells in EAE lesions as a source of fibroblast activation signals.

    “a scRNAseq analysis showed that fibroblasts from EAE lesions upregulate interferon γ (IFNγ) signaling, and conditional deletion of IFN receptor γ from fibroblasts partially blocked fibroblast expansion”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · hedged
      “IFNγ is produced by spinal cord T cells in EAE mice, implicating immune cells in EAE lesions as a source of fibroblast activation signals”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dorrier et al., 2021 source

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  • May combine two claims.

    Premisecitation

    Bacterial presence in the meninges induces a strong inflammatory response, including production of multiple cytokines (TNF-alpha, IL-1-beta, and IL-6), and a massive infiltration of neutrophils, and these cytokines and neutrophils work to quell the infection but also drive the breakdown of endothelial cell tight junctions.

    “Bacterial presence in the meninges induces a strong inflammatory response, including production of multiple cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, and IL-6), and a massive infiltration of neutrophils”
    • Also stated in: § Response of the Meninges to Meningitis · plain
      “The inflammatory cytokines and neutrophils work to quell the infection but also drive the breakdown of endothelial cell tight junctions”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mook-Kanamori et al., 2011 source

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    • cites Banerjee et al., 2011 source

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    Premisecitation

    In a subarachnoid hemorrhage model, erythrocytes accrue in the cervical lymph nodes via meningeal lymphatics following injury, and ablation of meningeal lymphatic vessels leads to less erythrocyte aggregation and greater neuroinflammation and neurological defects.

    “erythrocytes accrue in the cervical lymph nodes via meningeal lymphatics following injury, and ablation of meningeal lymphatic vessels leads to less erythrocyte aggregation and greater neuroinflammation and neurological defects”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chen et al., 2020 source

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    Premisecitation

    Using a Col1a1-GFP mouse line in conjunction with an EAE model, two independent groups identified substantial increases in fibroblasts within spinal cord lesion sites, and fibroblast expansion was deleterious for oligodendrocyte precursor cell (OPC) differentiation into mature oligodendrocytes and OPC migration into the lesion.

    “Using a Col1a1-GFP mouse line in conjunction with an EAE model, two independent groups identified substantial increases in fibroblasts within spinal cord lesion sites”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · plain
      “Fibroblast expansion was deleterious for oligodendrocyte precursor cell (OPC) differentiation into mature oligodendrocytes and OPC migration into the lesion”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Yahn et al., 2020 source

      Not checked in the free run.

    • cites Dorrier et al., 2021 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Biopsies taken from early MS patients with cortical demyelination were more likely to have leptomeningeal inflammation, consisting of effector T cells and IgA B cells infiltrates, than those without cortical demyelination, and the severity of cortical lesions is correlated to the extent of meningeal inflammation.

    “Biopsies taken from early MS patients with cortical demyelination were more likely to have leptomeningeal inflammation, consisting of effector T cells and IgA B cells infiltrates, than those without cortical demyelination.”
    • Also stated in: § Meninges and Perivascular Fibroblasts in Multiple Sclerosis · plain
      “in human cases of MS the severity of cortical lesions is correlated to the extent of meningeal inflammation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lucchinetti et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    All major meningitis causing bacteria can adhere strongly to meningeal fibroblasts and arachnoid barrier-like cells, and Group B Streptococcus bacteria cross the blood brain barrier by binding to vimentin on endothelial cells, which is also highly expressed by arachnoid barrier cells.

    “All major meningitis causing bacteria can adhere strongly to meningeal fibroblasts and arachnoid barrier-like cells”
    • Also stated in: § Response of the Meninges to Meningitis · plain
      “Group B Streptococcus bacteria cross the blood brain barrier by binding to vimentin on endothelial cells”
    • Also stated in: § Response of the Meninges to Meningitis · plain
      “Vimentin is also highly expressed by arachnoid barrier cells”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hardy et al., 2000 source

      Not checked in the free run.

    • cites Deng et al., 2019 source

      Not checked in the free run.

    • cites Weller et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer cells may enter the meninges via the choroid plexus, the brain, by crossing pial blood vessels or by vascular channels that connect the bone marrow and meninges.

    “Cancer cells may enter the meninges via the choroid plexus, the brain, by crossing pial blood vessels or by vascular channels that connect the bone marrow and meninges”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Redmer, 2018 source

      Not checked in the free run.

    • cites Yao et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer cells are able to grow in the nutrient deficient CSF filled leptomeninges using several notable mechanisms, such as tumor cells secreting complement component 3 which disrupts the barrier functions of choroid plexus epithelial cells, allowing nutrients and macromolecules to enter the CSF.

    “cancer cells are able to grow in the nutrient deficient CSF filled leptomeninges using several notable mechanisms”
    • Also stated in: § Meninges as a Site of Cancer Metastasis · plain
      “tumor cells present in the CSF secrete complement component 3”
    • Also stated in: § Meninges as a Site of Cancer Metastasis · plain
      “which disrupts the barrier functions of choroid plexus epithelial cells, allowing nutrients and macromolecules to enter the CSF”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Boire et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Breast cancer cells express ST6GALNAC5, which is normally exclusively expressed in the brain, allowing for increased adhesion to brain endothelial cells to pass through the BBB, and acute lymphoblastic leukemia cells access the CNS via vascular channels that exist between bone marrow located in the vertebral and calvarium bone and the meninges.

    “breast cancer cells express ST6GALNAC5, which is normally exclusively expressed in the brain, allowing for increased adhesion to brain endothelial cells to pass through the BBB”
    • Also stated in: § Meninges as a Site of Cancer Metastasis · plain
      “acute lymphoblastic leukemia cells access the CNS via vascular channels that exist between bone marrow located in the vertebral and calvarium bone and the meninges”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bos et al., 2009 source

      Not checked in the free run.

    • cites Yao et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proteolytic enzymes such as heparanase and seprase are important for the capacity of metastatic cells to traverse the BBB and occupy the brain, and micrometastases give rise to macrometastases through proliferation along brain microvessels.

    “proteolytic enzymes such as heparanase and seprase are important for the capacity of metastatic cells to traverse the BBB and occupy the brain”
    • Also stated in: § Meninges as a Site of Cancer Metastasis · plain
      “micrometastases give rise to macrometastases through proliferation along brain microvessels”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fazakas et al., 2011 source

      Not checked in the free run.

    • cites Kienast et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Impairment of meningeal lymphatics is a feature of AD and a potential therapeutic target.

    “Together this supports that impairment of meningeal lymphatics is a feature of AD and a potential therapeutic target.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    scRNAseq analysis done on tumor cells isolated from the leptomeninges of patients with metastatic growth showed high expression of the iron-binding protein lipocalin-2 (Lcn2) and its receptor SLC22A17, and Lcn2 expression, which is induced by macrophage cytokine release, allows tumor cells to grow more effectively in the low nutrient CSF environment.

    “scRNAseq analysis done on tumor cells isolated from the leptomeninges of patients with metastatic growth showed high expression of the iron-binding protein lipocalin-2 (Lcn2) its receptor SLC22A17”
    • Also stated in: § Meninges as a Site of Cancer Metastasis · plain
      “Lcn2 expression, which is induced by macrophage cytokine release, allows tumor cells to grow more effectively in the low nutrient CSF environment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chi et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    CSF is acellular, poor in protein, glucose and cytokine content, which is not conducive to cancer cell proliferation.

    “CSF is acellular, poor in protein, glucose and cytokine content, which is not conducive to cancer cell proliferation”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: CSF is acellular, poor in protein, glucose and cytokine content, which is not conducive to cancer cell proliferation.

  • May combine two claims.

    Premisecitation

    To cross the BBB, tumor cells bind endothelial cells and disrupt their tight junctions, and melanoma cells adhere to and disturb the interaction of brain endothelial cells through a disruption of tight and adherence junction proteins such as Claudin 5 and ZO-1.

    “To cross the BBB, tumor cells bind endothelial cells and disrupt their tight junctions”
    • Also stated in: § Meninges as a Site of Cancer Metastasis · plain
      “Melanoma cells adhere to and disturb the interaction of brain endothelial cells, which maintain the integrity of the BBB, through a disruption of tight and adherence junction proteins such as Claudin 5 and ZO-1.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bos et al., 2009 source

      Not checked in the free run.

    • cites Fazakas et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the APP/PS1 mouse model of AD, glymphatic dysfunction as measured by CSF clearance rates was impaired, and injection of amyloid-β into the CSF reduced glymphatic activity.

    “In the APP/PS1 mouse model of AD, glymphatic dysfunction as measured by CSF clearance rates was impaired”
    • Also stated in: § The Meninges and Alzheimer’s Disease · plain
      “injection of amyloid-β into the CSF reduced glymphatic activity”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Peng et al., 2016 source

      Not checked in the free run.

    • cites Wang L. et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is overwhelming evidence for cerebrovascular alterations in AD pathology and amyloid-β deposition around leptomeningeal vessels is a hall mark of cerebral amyloid angiopathy, occurring in almost all AD patients.

    “There is overwhelming evidence for cerebrovascular alterations in AD pathology and amyloid-β deposition around leptomeningeal vessels is a hall mark of cerebral amyloid angiopathy, occurring in almost all AD patients”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Greenberg et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Primary tumors of the meninges are quite rare, however, the leptomeninges is a relatively common site for contiguous extension of primary tumors of the central nervous system, paranasal sinuses and skull base origin or tumor metastasis which can lead to dissemination into the CNS parenchyma and poor prognosis.

    “Primary tumors of the meninges are quite rare, however, the leptomeninges is a relatively common site for by contiguous extension of primary tumors of the central nervous system, paranasal sinuses and skull base origin or tumor metastasis which can lead to dissemination into the CNS parenchyma and poor prognosis”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Mahendru and Chong, 2009

      Not checked in the free run.

    • cites Waki et al., 2009 source

      Not checked in the free run.

    • cites Oechsle et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disruption of meningeal lymphatic vessels promotes amyloid-β deposition, in both the brain and meninges, while the rescue of age-induced meningeal lymphatic defects improved cognitive performance.

    “disruption of meningeal lymphatic vessels promotes amyloid-β deposition, in both the brain and meninges”
    • Also stated in: § The Meninges and Alzheimer’s Disease · plain
      “the rescue of age-induced meningeal lymphatic defects improved cognitive performance”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Da Mesquita et al., 2018b

      Not checked in the free run.

    • cites Wang L. et al., 2019

      Not checked in the free run.

49 of 49

  • The paper relies on this without support.

    The degree of neuroinflammation following acute CNS injury is a major predictor of clinical outcomes.

    “The degree of neuroinflammation following acute CNS injury is a major predictor of clinical outcomes”

  • The paper relies on this without support.

    CSF is acellular, poor in protein, glucose and cytokine content, which is not conducive to cancer cell proliferation.

    “CSF is acellular, poor in protein, glucose and cytokine content, which is not conducive to cancer cell proliferation”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • VLMC types show highly specific spatial and colocalization patterns.

    “VLMC types66,82 also show highly specific spatial and colocalization patterns.”

    From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [82]

    The Fibroblasts section (page unavailable) describes meningeal fibroblast populations in distinct layers and perivascular fibroblasts beside particular blood vessels, supporting spatial specificity. It does not establish highly specific colocalization patterns for VLMC types; the Conclusion (page unavailable) says there is a lack of consensus on these populations’ spatial heterogeneity. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Interactions between various VLMC and ependymal cell clusters, together with ABCs, likely regulate the movement of molecules and cells across the barriers between brain and blood or CSF.

    “Interactions between various VLMC and ependymal cell clusters, together with ABCs, likely regulate the movement of molecules and cells across the barriers between brain and blood or CSF82.”

    From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [82]

    The Meningeal Cell Types section and Figure 2 describe arachnoid barrier cells regulating the movement of molecules and cells between the dura and CSF-filled subarachnoid space. The Conclusion mentions vascular leptomeningeal cell clusters, but the cited passages do not establish that interactions among VLMC and ependymal cell clusters, together with arachnoid barrier cells, regulate that movement. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

4 of the 209 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A.
Affiliations
University of Colorado Anschutz (US)
Corresponding author
  • Derk, Julia
  • Siegenthaler, Julie A.
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2021-07-01
Volume
15
Pages
703944-703944
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2021.703944
PMC
PMC8281977
OpenAlex
W3183553035
Semantic Scholar
2966a8fcf8ac4fde0aeecca0729e94168bb52f39
Cited by
120
References
209
Citations by year
2026: 11 · 2025: 23 · 2024: 28 · 2023: 36 · 2022: 22
FWCI
2.51
Type
journal article
Language
en
Update notices
corrigendum (2021-10-08)
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
meninges, dura mater, pia mater, meningeal lymphatic system, meningeal immune cells, blood-CSF barrier, multiple sclerosis, dementia, stroke, bacterial meningitis, viral meningitis, traumatic brain injury

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

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