Meningeal Lymphatics Research Articles

Lymph Flow Induces the Postnatal Formation of Mature and Functional Meningeal Lymphatic Vessels.

Recently, the presence of lymphatics has been demonstrated and characterized in the dura mater, which is in contrast to the well-accepted view indicating the lack of a classical lymphatic drainage system of the central nervous system (CNS). Moreover, the role of meningeal lymphatics in the pathogenesis of Alzheimer's disease and multiple sclerosis was suggested. However, the possible regulators of the developmental program and function of meningeal lymphatics remain unclear. Here, we aimed at characterizing the lymph flow dependence of the developmental program and function of the meningeal lymphatics. First, we demonstrated that lymphatics present in the dura mater are involved in the uptake and transport of macromolecules from the CNS. Meningeal lymphatics develop during the postnatal period which process involves the maturation of the vessels. The formation of mature meningeal lymphatics coincides with the increase of the drainage of macromolecules from the CNS to the deep cervical lymph nodes. Importantly, the structural remodeling and maturation of meningeal lymphatics is impaired in Plcγ2−/− mice with reduced lymph flow. Furthermore, macromolecule uptake and transport by the meningeal lymphatics are also affected in Plcγ2−/− mice. Collectively, lymph flow-induced mechanical forces are required for the postnatal formation of mature and functional meningeal lymphatic vessels. Defining lymph flow-dependence of the development and function of meningeal lymphatics may lead to better understanding of the pathogenesis of neurological diseases including Alzheimer's disease and multiple sclerosis.

Meningeal Lymphatic Pathway of Brain Clearing From the Blood After Haemorrhagic Injuries.

This seems to be the time to gain new knowledge about the meningeal lymphatic system and a deeper understanding of its anatomy and physiology. Although it is known that the meningeal lymphatics present in the layers of the brain, limited information is available about the role of this system in brain function. Here, for the first time we clearly demonstrate that the meningeal lymphatic pathway is involved in brain clearing from the blood after intracranial hemorrhage associated with hypoxia and forms a connective bridge between interstitial, cerebral spinal fluid and peripheral lymphatics. We also show that the development of methods to stimulate meningeal lymph flow after hemorrhagic evidence in the brain might be a neuroprotective strategy for effective recovery of the brain after a cerebrovascular catastrophe.

Meningeal lymphatics, immunity and neuroinflammation.

In the past five years, the surrounding of the brain, that is the meninges (singular meninx) have evolved from being a physical barrier that protects the brain parenchyma to becoming a central player for both the maintenance of normal brain function and the modulation of neurological disorders. Indeed, the meninges are an immunologically active compartment that communicates with the periphery via the (re)discovered meningeal lymphatic system. From its ties to both the periphery and the central nervous system, the meninges are becoming a prevalent organ to understand and modulate brain homeostasis. Here we will focus on current advances in our understanding of the meningeal compartment with an emphasis on the meningeal lymphatic network as a key regulator.

Meningeal Lymphatics: A Review and Future Directions From a Clinical Perspective.

The recent discovery of lymphatic vessels in the meningeal layers calls into question the known mechanisms of fluid and macromolecule homeostasis and immunoregulation within the central nervous system. These meningeal lymphatic vessels and their potential role in the pathophysiology of neurological disease have become a rapidly expanding area of research, with the hopes that they may provide a novel therapeutic target in the treatment of many devastating conditions. This article reviews the current state of knowledge surrounding the anatomical structure of the vessels, their functions in fluid and solute transport and immune surveillance, as well as their studied developmental biology, relationship with the novel hypothesized “glymphatic” system, and implications in neurodegenerative disease in animal models. Furthermore, this review summarizes findings from the human studies conducted thus far regarding the presence, anatomy, and drainage patterns of meningeal lymphatic vessels and discusses, from a clinical perspective, advancements in both imaging technologies and interventional methodologies used to access ultrafine peripheral lymphatic vessels.

Complex Non-sinus-associated Pachymeningeal Lymphatic Structures: Interrelationship With Blood Microvasculature.

The contribution of cranial dura mater vascular networks, as means for maintaining brain fluid movement and balance, and as the source of significant initiators and/or contributors to neurological disorders, has been overlooked. These networks consist of both blood and lymphatic vessels. The latter were discovered recently and described as sinus-associated structures thus changing the old paradigm that central nervous system lacks lymphatics. In this study, using markers specific to blood and lymphatic endothelia, we demonstrate the existence of the complex non-sinus-associated pachymeningeal lymphatic vasculature. We further show the interrelationship and possible connections between lymphatic vessels and the dural blood circulatory system. Our novel findings reveal the presence of lymphatic-like structures that exist on their own and/or in close proximity to microvessels. Of particular interest are sub-sets of vascular complexes with dual (lymphatic and blood) vessel identity representing a unique microenvironment within the cranial dura. The close association of the systemic blood circulation and meningeal lymphatics achieved in these complexes could facilitate fluid exchange between the two compartments and constitute an alternative route for CSF drainage.

The Space between the Pial Sheath and the Cortical Venous Wall May Connect to the Meningeal Lymphatics.

We currently obtain pre- and post-contrast enhanced whole brain 3D-real inversion recovery images for the evaluation of endolymphatic hydrops. We noticed that the space between the pial sheath surrounding the cortical veins and the cortical venous wall is enhanced and this enhancement seems to connect to the meningeal lymphatics along superior sagittal sinus. This new anatomical concept regarding the outflow from the glymphatic system might be important for the future research in neuroscience.

Neurofluids: A holistic approach to their physiology, interactive dynamics and clinical implications for neurological diseases

There is increasing interest in understanding the physiology of the extracellular fluid compartments in the central nervous system and their dynamic interaction. Such interest has been in part prompted by a vigorous resurgence of the role of the venous system, the recent discoveries of the meningeal lymphatics, the brain waste removal mechanisms and their potential link to neurological diseases, such as idiopathic intracranial hypertension, Ménière’s disease, migraine, small vessel disease, and most neurodegenerative diseases. The rigid cranial cavity houses several space-competing material compartments: the brain parenchyma (BP) and four extracellular fluids, namely arterial, venous, cerebrospinal fluid (CSF) and interstitial fluid (ISF). During cardiac pulsations, the harmonious, temporal and spatial dynamic interaction of all these fluid compartments and the BP assures a constant intracranial volume at all times, consistent with the Monro-Kellie hypothesis. The dynamic interaction involves high-pressure input of arterial blood during systole and efflux of CSF into the spinal subarachnoid space (SSAS) followed by venous blood exiting directly into the vertebral and internal jugular veins towards the heart and intraventricular CSF displacing caudally towards the SSAS. Arterial pulsatile energy is transmitted to the BP that contributes to the smooth movement of fluids in and out of the brain. Perturbing any of these fluid compartments will alter the entire brain dynamics, potentially increase intracranial pressure, affect perfusion and hamper clearance capacity of metabolic waste. This review of all major extracellular fluid compartments within the brain, advocates a holistic approach to our understanding of the fluid dynamics, rather than focusing on a single compartment when analyzing neurological diseases. This approach may contribute to advance our comprehension of some common neurological disorders, paving the way to newer treatment options.

Connections Between Amyloid Beta and the Meningeal Lymphatics As a Possible Route for Clearance and Therapeutics.

Alzheimer's disease (AD) is a complex neurodegenerative disorder causing progressive cognitive decline, memory loss, and death of neural tissue. Current research suggests a connection between bulk flow of interstitial fluid and cerebrospinal fluid across the blood-brain barrier and the recently confirmed meningeal lymphatic channels of the brain. The main symptom of interest in AD is the spontaneous aggregation of amyloid beta (Aβ) proteins resulting from increased production or lack of clearance from brain tissues. These protein aggregates manifest as plaques in the capillary and artery lumina and the neuronal and dural tissues of the brain, and are known to contribute to cerebral amyloid angiopathy and a host of other neuroinflammatory conditions. The meningeal lymphatics contain a substantial population of immune cells and also serve as a drain into the deep cervical lymph nodes. In this study we discuss the molecular mechanisms by which Aβ could gain access to meningeal lymphatic channels through the blood-brain interface, including ways in which it can be cleared to preclude aggregation and plaque deposition.

On the Right Track: Meningeal Lymphatics Guide Angiogenesis during Tissue Repair in the Brain

Recent studies of brain meningeal lymphatic endothelial cells in mouse and zebrafish have raised interest in their function. In this issue of Developmental Cell, Chen etal. (2019) reveal new developmental roles for these cells in facilitating tissue repair and guiding vascular re-growth in the central nervous system.

Neuroinflammation functionally regulates CNS lymphatic vasculature and drainage

Abstract There are no conventional lymphatic vessels within the CNS parenchyma, although it has been hypothesized that lymphatics near the cribriform plate or dura maintain fluid homeostasis and immune surveillance during steady-state conditions. However, the role of these lymphatic vessels during neuroinflammation is not well understood. We report that lymphatic vessels near the cribriform plate undergo lymphangiogenesis in a VEGFC – VEGFR3 dependent manner during experimental autoimmune encephalomyelitis (EAE) and drain both CSF and cells that were once in the CNS parenchyma. Lymphangiogenesis also contributes to the drainage of CNS derived antigens that leads to antigen specific T cell proliferation in the draining lymph nodes during EAE. In contrast, meningeal lymphatics do not undergo lymphangiogenesis during EAE, suggesting heterogeneity in CNS lymphatics. We conclude that increased lymphangiogenesis near the cribriform plate can contribute to the management of neuroinflammation-induced fluid accumulation and immune surveillance.

Cerebrovascular Injuries Induce Lymphatic Invasion into Brain Parenchyma to Guide Vascular Regeneration in Zebrafish

Damage to regional cerebrovascular networks and neuronal tissues occurs during acute cerebrovascular diseases, such as ischemic stroke. The promotion of vascular regeneration is the most promising therapeutic approach. To understand the cellular and molecular mechanisms underlying brain vascular regeneration, we developed two zebrafish cerebrovascular injury models using genetic ablation and photochemical thrombosis. Although brain parenchyma is physiologically devoid of lymphatic vasculature, we found that cerebrovascular injuries induce rapid ingrowth of meningeal lymphatics into the injured parenchyma. The ingrown lymphatics on one hand become lumenized to drain interstitial fluid to resolve brain edema and on the other hand act as "growing tracks" fornascent blood vessels. The ingrown lymphatic vesselsundergo apoptosis and clearance after cerebrovascular regeneration. This study reveals a pathological function of meningeal lymphatics, through previously unexpected ingrowth into brain parenchyma and a newly identified lymphatic function as vascular "growing tracks."

Abstract TMP27: Laser Stimulation of Brain Drainage and Recovery After Hemorrhagic Stroke

In our previous data we observed the presence of products of degraded blood (the iron/hemosiderin) in the meningeal lymphatics (ML) and in the deep cervical lymph node (dcLN) in patients who died after hemorrhagic events (brain trauma and stroke). Here we demonstrate novel data related to the brain clearance from the blood after hemorrhagic stroke (HeStr) via the ML in rats. For the first time, we show non-invasive laser method for stimulation of ML drainage for the brain recovery after HeStr using laser irradiation though the intact skull and skin. Experiments were carried out in adult mongrel rats (250-280 g) using model of HeStr. All procedures were performed in accordance with the “Position of the American Heart Association on Research Animal Use“ (Circulation 1985; 71:849A). The new generation laser 1268 nm (30 nm, 7 min) was used for stimulation of the ML drainage through the intact skull and skin that was analyzed in vivo (two-photon, fluorescent, optical coherent tomography imaging) and ex vivo (immunohistochemical, confocal data) using markers of lymphatic endothelium (LYVE-1/LYVE-1 conjugated with Alexa 488 and Prox-1). The results clearly demonstrated that 1h after HeStr the iron/hemosiderin (detected by atomic absorption spectroscopy and histological method) accumulated in the dcLN and observed in the ML. The laser application caused stimulation of the ML drainage (analyzed by dextran movement in vivo) and was accompanied by decrease in the iron/hemosiderin level in the brain tissues with an appropriate increase of their level in the dcLN. The application of laser (one time a day) during one week contributed a better recovery after HeStr vs. the control group (without laser) that was confirmed by analysis of inflammatory factors (C-reactive protein, IL-6 and lipoprotein-associated phospholipase A2, immunoassay analysis), macrophages infiltration (confocal imaging), edema, necrotic and ischemic events (histological data). In sum, our results suggest that laser 1268 nm by stimulation of endogenous processes of brain lymphatic drainage might be a novel auxiliary non-invasive method for brain recovery after HeStr. The research was supported by grant of Russian Science Foundation No 17-15-01263.

Neuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells

There are no conventional lymphatic vessels within the CNS parenchyma, although it has been hypothesized that lymphatics near the cribriform plate or dura maintain fluid homeostasis and immune surveillance during steady-state conditions. However, the role of these lymphatic vessels during neuroinflammation is not well understood. We report that lymphatic vessels near the cribriform plate undergo lymphangiogenesis in a VEGFC – VEGFR3 dependent manner during experimental autoimmune encephalomyelitis (EAE) and drain both CSF and cells that were once in the CNS parenchyma. Lymphangiogenesis also contributes to the drainage of CNS derived antigens that leads to antigen specific T cell proliferation in the draining lymph nodes during EAE. In contrast, meningeal lymphatics do not undergo lymphangiogenesis during EAE, suggesting heterogeneity in CNS lymphatics. We conclude that increased lymphangiogenesis near the cribriform plate can contribute to the management of neuroinflammation-induced fluid accumulation and immune surveillance.

Impaired meningeal lymphatic vessel development worsens stroke outcome

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3wt/mut mice develop significantly fewer meningeal LVs than Vegfr3wt/wt mice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke in Vegfr3wt/wt mice. Interestingly, Vegfr3wt/mut mice develop larger stroke volumes than Vegfr3wt/wt mice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes.

Lymphatic system in central nervous system

The considerable metabolic activity of the central nervous system (CNS) requires an efficient system of tissue drainage and detoxification. The CNS is however devoid of lymphatic vessels, a vasculature ensuring interstitial fluid drainage and immune survey in other organs. A unique system of drainage has recently been identified between the cerebrospinal fluid (CSF), brain interstitial fluids and meningeal lymphatic vessels. This system is coupling a cerebral "glymphatic" flow with a meningeal lymphatic vasculature. The "glymphatic" system includes perivascular spaces and astrocytes, and drains interstitial fluids, from and towards the CSF. Meningeal lymphatic vessels are functionally linked to the cerebral "glymphatic" efflux by clearing intracerebral macromolecules and antigens towards the peripheral lymphatic system. The "glymphatic"-"meningeal lymphatics" system is potentially offering new therapeutic targets to improve cerebral drainage and immune survey in human CNS diseases.

Neurodegenerative Dementias: Improving Brain Health to Decrease Risk.

Neurodegenerative Dementias: Improving Brain Health to Decrease Risk.

The Importance of Keeping Your Brain's Pipes Clean: The role of Meningeal Lymphatics in Ageing and Alzheimer's Disease.

The Importance of Keeping Your Brain's Pipes Clean: The role of Meningeal Lymphatics in Ageing and Alzheimer's Disease.

Our current understanding of the lymphatics of the brain and spinal cord.

The lymphatic system, segregated from the blood vascular system, is an essential anatomical route along which interstitial fluid, solutes, lipids, immune cells, and cellular debris, are conveyed. However, the way these mechanisms operate within the cranial compartment is mostly unknown. Herein, we review current understanding of the meningeal lymphatics, described anatomically over a century ago yet still poorly understood from a functional standpoint. We will delineate the cellular mechanisms by which the meningeal lymphatics are formed and discuss their unique anatomy. Furthermore, this review will discuss the recently-coined "glymphatic system" and the manner by which cerebrospinal fluid (CSF) and interstitial fluid (ISF) are exchanged and thus drained by the meningeal lymphatic vasculature as a key route for conveying cellular waste, solutes, and immune traffic to the deep cervical lymph nodes. The clinical relevance of the meningeal lymphatics will also be described, as they are relevant to various common defects of the lymphatic system. Clin. Anat. 32:117-121, 2019. © 2018 Wiley Periodicals, Inc.

The CNS Immune-Privilege Goes Down the Drain(age)

Ongoing research is revealing multiple, previously unappreciated, facets of immunity in the central nervous system, and the recent studies on the meningeal lymphatic system represent an emblematic example. In this context, a paper from Louveau and colleagues (Nat. Neurosci. 2018;21:1380-1391), which we discuss here, elucidates the importance of the meningeal lymphatics for the drainage of macromolecules and immune cells from the cerebrospinal fluid, and their delivery into the cervical lymph nodes, especially during neuroinflammatory diseases.

Meningeal lymphatics in aging and Alzheimer’s disease

Meningeal lymphatics in aging and Alzheimer’s disease