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

The DOI matches its Crossref record; 205 of the 209 references it cites were found in a registry or an index; 1 of the 111 sources its claims cite were checked for support.

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

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.

Overview

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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.

Figures

FIGURE 1 Meninges structure and cellular heterogeneity (A) Schematic of cellular make up and structure of the mouse meninges and contiguous perivascular space. (B) Electron microscopy image of a human arachnoid trabecula, the collagen fibril structures that span the wide of the sub-arachnoid space. A cell, potentially an arachnoid, is seen associated with the collagen fibril. Image reproduced with permission from Alcolado et al. (1988). (C) Electron microscopy image of the mouse leptomeninges, a “pia-arachnoid” cell process (PA) spans the subarachnoid space (SA) containing blood vessels (BV). Cells of the inner arachnoid are immediately adjacent to the arachnoid barrier cell layer, which contains microfibrils (f) of extracellular matrix material. Image reproduced with permission from McLone and Bondareff (1975). (D) Immunofluorescence image of human fetal leptomeninges in the Sylvian sulcus labeled with CRABP2 (magenta) and DAPI (cyan). CRABP2 immunoreactivity in the meninges is limited to the arachnoid layer and cells associated with the arachnoid trabecula (AT) in the subarachnoid space (SA). Image reproduced with permission from DeSisto et al. (2020). BV, blood vessels. (E) Immunofluorescence image of mouse leptomeninges at postnatal day 14 labeled with CRABP2 (magenta) and DAPI (cyan). CRABP2 immunoreactivity is seen in cells of the arachnoid layer but not in pia-located cells. Image reproduced with permission from DeSisto et al. (2020).
FIGURE 1 Meninges structure and cellular heterogeneity (A) Schematic of cellular make up and structure of the mouse meninges and contiguous perivascular space. (B) Electron microscopy image of a human arachnoid trabecula, the collagen fibril structures that span the wide of the sub-arachnoid space. A cell, potentially an arachnoid, is seen associated with the collagen fibril. Image reproduced with permission from Alcolado et al. (1988). (C) Electron microscopy image of the mouse leptomeninges, a “pia-arachnoid” cell process (PA) spans the subarachnoid space (SA) containing blood vessels (BV). Cells of the inner arachnoid are immediately adjacent to the arachnoid barrier cell layer, which contains microfibrils (f) of extracellular matrix material. Image reproduced with permission from McLone and Bondareff (1975). (D) Immunofluorescence image of human fetal leptomeninges in the Sylvian sulcus labeled with CRABP2 (magenta) and DAPI (cyan). CRABP2 immunoreactivity in the meninges is limited to the arachnoid layer and cells associated with the arachnoid trabecula (AT) in the subarachnoid space (SA). Image reproduced with permission from DeSisto et al. (2020). BV, blood vessels. (E) Immunofluorescence image of mouse leptomeninges at postnatal day 14 labeled with CRABP2 (magenta) and DAPI (cyan). CRABP2 immunoreactivity is seen in cells of the arachnoid layer but not in pia-located cells. Image reproduced with permission from DeSisto et al. (2020).CC BY · PubMed Central
FIGURE 2 Function and structure of the arachnoid barrier layer in the meninges. (A) Graphical depiction of proposed functions of the arachnoid barrier layer of the meninges including (1) as a physical barrier preventing free movement of molecules and cells into the subarachnoid space by virtue of its tight junctions, (2) enriched expression of efflux (P-glycoprotein, BCRP) and solute transporters (SLC) by arachnoid barrier cells support regulated movement of molecules across this barrier layer. (B) Electron microscopy image of the mouse arachnoid-dura interface, reproduced with permission from Nabeshima et al. (1975). Pseudo-coloring of the cell bodies highlights close interface between cells of the arachnoid (A) (inner arachnoid fibroblasts and arachnoid barrier cells connected by electron-dense tight junctions) and cells of the dura, [dura border cells (Db) and dural fibroblasts within collagen fibril dense dura layer]. (C) Immunofluorescence image of mouse leptomeninges from a postnatal day 14 Col1a1-GFP mouse brain with E-cadherin (magenta) and DAPI (cyan). E-cadherin is expressed by arachnoid barrier cells (representing the outer part of the arachnoid layer) but not by inner Col1a1-GFP+ fibroblasts, representing pial and inner arachnoid fibroblasts. Image reproduced with permission from DeSisto et al. (2020).
FIGURE 2 Function and structure of the arachnoid barrier layer in the meninges. (A) Graphical depiction of proposed functions of the arachnoid barrier layer of the meninges including (1) as a physical barrier preventing free movement of molecules and cells into the subarachnoid space by virtue of its tight junctions, (2) enriched expression of efflux (P-glycoprotein, BCRP) and solute transporters (SLC) by arachnoid barrier cells support regulated movement of molecules across this barrier layer. (B) Electron microscopy image of the mouse arachnoid-dura interface, reproduced with permission from Nabeshima et al. (1975). Pseudo-coloring of the cell bodies highlights close interface between cells of the arachnoid (A) (inner arachnoid fibroblasts and arachnoid barrier cells connected by electron-dense tight junctions) and cells of the dura, [dura border cells (Db) and dural fibroblasts within collagen fibril dense dura layer]. (C) Immunofluorescence image of mouse leptomeninges from a postnatal day 14 Col1a1-GFP mouse brain with E-cadherin (magenta) and DAPI (cyan). E-cadherin is expressed by arachnoid barrier cells (representing the outer part of the arachnoid layer) but not by inner Col1a1-GFP+ fibroblasts, representing pial and inner arachnoid fibroblasts. Image reproduced with permission from DeSisto et al. (2020).CC BY · PubMed Central
FIGURE 3 Meningeal cells or structures in CNS injury and disease. (A) Depiction of CNS injury or diseases in which meningeal cells, meninges located cell types or parenchyma located perivascular fibroblasts are part of the pathology. SCI, spinal cord injury; TBI, traumatic brain injury; EAE, experimental autoimmune encephalomyelitis. (B) Graphical depiction of fibrosis, caused by increased meningeal/perivascular fibroblast proliferation and Extracellular matrix (ECM) deposition and summary of known CNS fibroblast-derived factors identified in specific CNS disease states. AD, Alzheimer’s disease. (C) Summary of functional roles of meningeal-located immune cells in specific CNS disease states. B-CSFB, blood-CSF barrier. (D) Summary of cellular changes in meninges located lymphatic vasculature in response to different CNS injuries and disease states.
FIGURE 3 Meningeal cells or structures in CNS injury and disease. (A) Depiction of CNS injury or diseases in which meningeal cells, meninges located cell types or parenchyma located perivascular fibroblasts are part of the pathology. SCI, spinal cord injury; TBI, traumatic brain injury; EAE, experimental autoimmune encephalomyelitis. (B) Graphical depiction of fibrosis, caused by increased meningeal/perivascular fibroblast proliferation and Extracellular matrix (ECM) deposition and summary of known CNS fibroblast-derived factors identified in specific CNS disease states. AD, Alzheimer’s disease. (C) Summary of functional roles of meningeal-located immune cells in specific CNS disease states. B-CSFB, blood-CSF barrier. (D) Summary of cellular changes in meninges located lymphatic vasculature in response to different CNS injuries and disease states.CC BY · PubMed Central

Verification

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    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”
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    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”
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Metadata

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.
Venue
Frontiers in Cellular Neuroscience
Published
2021-07-01
Volume
15
Pages
703944-703944
ISSN
1662-5102 (ISSN-L)
OpenAlex
W3183553035
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
Open access
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
  • Health Sciences › Medicine › Clinical Neurology › 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

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