![Gray488](https://upload.wikimedia.org/wikipedia/commons/1/1c/Gray488.png)
The meningeal lymphatic vessels (or meningeal lymphatics) are a network of conventional
lymphatic vessel
The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vess ...
s located parallel to the
dural venous sinuses
The dural venous sinuses (also called dural sinuses, cerebral sinuses, or cranial sinuses) are venous channels found between the endosteal and meningeal layers of dura mater in the brain. They receive blood from the cerebral veins, receive cereb ...
and
middle meningeal arteries
The middle meningeal artery ('' la, arteria meningea media'') is typically the third branch of the maxillary artery#First portion, first portion of the maxillary artery. After branching off the maxillary artery in the infratemporal fossa, it runs t ...
of the mammalian
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS). As a part of the
lymphatic system
The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...
, the meningeal lymphatics are responsible for draining
immune cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
, small molecules, and excess fluid from the CNS into the
deep cervical lymph nodes
The deep cervical lymph nodes are a group of cervical lymph nodes found near the internal jugular vein in the neck.
Structure
The deep cervical lymph nodes can be divided into upper and lower groups, or superior and inferior groups.
Alternati ...
.
Cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
, and
interstitial fluid
In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...
are exchanged, and drained by the meningeal lymphatic vessels.
While it was historically believed that both the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
and
meninges
In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...
were devoid of lymphatic vasculature, recent studies by Antoine Louveau and
Jonathan Kipnis at the
University of Virginia
The University of Virginia (UVA) is a Public university#United States, public research university in Charlottesville, Virginia. Founded in 1819 by Thomas Jefferson, the university is ranked among the top academic institutions in the United S ...
, submitted in October 2014, and by Aleksanteri Aspelund, Salli Antila and
Kari Alitalo at the
University of Helsinki
The University of Helsinki ( fi, Helsingin yliopisto, sv, Helsingfors universitet, abbreviated UH) is a public research university located in Helsinki, Finland since 1829, but founded in the city of Turku (in Swedish ''Ã…bo'') in 1640 as the ...
submitted in December 2014, identified and described the basic biology of the meningeal lymphatics using a combination of
histological
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
,
live-imaging, and
genetic tools.
[ In general, their work is thought to extend that of the Danish neuroscientist Maiken Nedergaard in identifying the pathway connecting the ]glymphatic system
The glymphatic system (or glymphatic clearance pathway, or paravascular system) was described and named in 2013 as a system for waste clearance in the central nervous system (CNS) of vertebrates. According to this model, cerebrospinal fluid (CSF) ...
to the meningeal compartment.
The role that the meningeal lymphatics plays in neurological disease is yet to be explored. It is hypothesized that they may contribute to autoimmune and inflammatory diseases of the CNS due to their role in connecting the immune
In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...
and nervous systems.
Background
In peripheral organs, lymphatic vessels
The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vessel ...
are responsible for conducting lymph
Lymph (from Latin, , meaning "water") is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues to ...
between different parts of the body. In general, lymphatic drainage is important for maintaining fluid homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
as well as providing a means for immune cells to traffic into draining lymph nodes
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
from other parts of the body, allowing for immune surveillance of bodily tissues.
The first mention of meningeal lymphatic vessels can be attributed to Paolo Mascagni
Paolo Mascagni (25 January 1755 – 19 October 1815) was an Italian physician and anatomist. He is most well known for publishing the first complete description of the lymphatic system.
Biography Early life
Mascagni was born in the co ...
, whose anatomical work towards the end of the eighteenth century suggested their presence; however, this work received little attention or acceptance.[ In 1953, Italian scientist Lecco identified putative lymphatic vessels in ]post-mortem
An autopsy (post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death or to evaluate any dis ...
human dura. Further research in the 1960s described the existence of meningeal lymphatics, but these findings were not accepted by the field due to their limited methodology.
Prior to the discovery of true meningeal lymphatic vessels, it was generally believed that the mammalian CNS did not contain a lymphatic system and thus relied upon alternative routes of waste clearance such as the glymphatic system
The glymphatic system (or glymphatic clearance pathway, or paravascular system) was described and named in 2013 as a system for waste clearance in the central nervous system (CNS) of vertebrates. According to this model, cerebrospinal fluid (CSF) ...
, a cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
(CSF) drainage pathway under the cribriform plate
In mammalian anatomy, the cribriform plate (Latin for lit. ''sieve-shaped''), horizontal lamina or lamina cribrosa is part of the ethmoid bone. It is received into the ethmoidal notch of the frontal bone and roofs in the nasal cavities. It supp ...
and into the lymphatics of the nasal mucosa
The nasal mucosa lines the nasal cavity. It is part of the respiratory mucosa, the mucous membrane lining the respiratory tract. The nasal mucosa is intimately adherent to the periosteum or perichondrium of the nasal conchae. It is continuous w ...
, and arachnoid granulations to clear itself of excess protein, fluid, and metabolic waste products. Furthermore, the presumed absence of CNS lymphatics was an important pillar in the long-held dogma that the CNS is an immune-privileged tissue to which immune cells have highly restricted access under normal physiological conditions.
Discovery
Although, several studies proposed the existence of lymphatic vessels in the dura mater, the presence of the meningeal lymphatic system was accepted in 2015, when two independent studies published by Louveau et al. and Aspelund et al. provided convincing data using novel methods. Louveau et al. noticed an unusual alignment of immune cells along the dural sinus using a meningeal whole-mount technique. Using lymphatic endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
-specific markers and electron microscopy
An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
, the authors found that the immune cells were not inside blood vessels, but rather were organized inside lymphatic vessels within the meninges
In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...
, a system of membranes that envelop the brain and spinal cord.
Aspelund et al. had discovered that in the eye, another immune-privileged organ, the Schlemm's canal
Schlemm's canal is a circular lymphatic-like vessel in the eye. It collects aqueous humor from the anterior chamber and delivers it into the episcleral blood vessels. Canaloplasty may be used to widen it.
Structure
Schlemm's canal is an endot ...
is a lymphatic-like vessel. As Schlemm's canal was previously considered to be a venous sinus, the authors subsequently hypothesized that similar vessels may also be found in the brain due to its similarly immune-privileged status.[ However, a recent study reported the absence of lymphatic vessels in the spinal cord dura of rat despite harboring numerous LYVE1+ cells.
In an interview with ]Ira Flatow
Ira Flatow (; born March 9, 1949) is a radio and television journalist and author who hosts Public Radio International's popular program ''Science Friday''. On TV, he hosted the Emmy Award-winning PBS series ''Newton's Apple'', a television scie ...
on NPR's Science Friday
''Science Friday'' (known as ''SciFri'' for short) is a weekly call-in talk show that broadcasts each Friday on public radio stations, distributed by WNYC Studios, and carried on over 400 public radio stations. ''SciFri'' is hosted by award-win ...
, Kipnis described the meningeal lymphatics as "well-hidden" when asked how, unlike the rest of the lymphatic system, they had remained unmapped into the 21st century. While many scientists study the brain parenchyma
Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms.
Etymology
The term ''parenchyma'' is New Latin from the word π ...
proper, Kipnis explained, his lab is relatively unique in studying the meninges:
Visualization
To visualize the dura mater
In neuroanatomy, dura mater is a thick membrane made of dense irregular connective tissue that surrounds the brain and spinal cord. It is the outermost of the three layers of membrane called the meninges that protect the central nervous system. ...
using immunohistochemistry
Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
, the dura must first be fixed
Fixed may refer to:
* ''Fixed'' (EP), EP by Nine Inch Nails
* ''Fixed'', an upcoming 2D adult animated film directed by Genndy Tartakovsky
* Fixed (typeface), a collection of monospace bitmap fonts that is distributed with the X Window System
* ...
within the skullcap. It is prepared by cutting around the base of the skull (inferior to the post-tympanic hook) and removing the lower portion of the skull and brain. Following fixation, the dura can be dissected out of the skullcap as a single piece of tissue that can be utilized for histological analysis.
In transgenic mice containing ''Prox1-GFP'' or ''Vegfr3-LacZ'' reporter genes, the lymphatic vessels may be visualized by fluorescent microscopy or after X-gal staining, respectively.[
The meningeal lymphatics may also be visualized non-invasively by ]MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
, using MRI contrast agent
MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten ...
s such as gadobutrol and gadofosveset to reveal the presence of the vessels near the dura mater.
Biology
Anatomy and route of drainage
The meningeal lymphatic system is composed of a network of vessels along the dural sinus in the dura which express lymphatic endothelial cell marker proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
, including PROX1
Prospero homeobox protein 1 is a protein that in humans is encoded by the ''PROX1'' gene. The Prox1 gene is critical for the development of multiple
tissues. Prox1 activity is necessary and sufficient to specify a lymphatic endothelial cell fate i ...
, LYVE1
Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), also known as extracellular link domain containing 1 (XLKD1) is a Link domain-containing hyaladherin, a protein capable of binding to hyaluronic acid (HA), homologous to CD44, the main ...
, and PDPN
Podoplanin is a protein that in humans is encoded by the ''PDPN'' gene.
Structure and function
Podoplanin is a mucin-type protein with a mass of 36- to 43-kDa. It is relatively well conserved between species, with homologues in humans, mice, rat ...
. The vessels extend along the length of both the superior sagittal and transverse sinuses and directly connects to the deep cervical lymph nodes. These meningeal lymphatic vessels drain down and exit the skull along the dural venous sinuses and meningeal arteries. Meningeal lymphatic vessels also drain out of the skull alongside cranial nerves
Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and f ...
and through the cribriform plate
In mammalian anatomy, the cribriform plate (Latin for lit. ''sieve-shaped''), horizontal lamina or lamina cribrosa is part of the ethmoid bone. It is received into the ethmoidal notch of the frontal bone and roofs in the nasal cavities. It supp ...
. Molecular profiling indicates that the vessels are conventional lymphatic vessels: they express high levels of PROX1, LYVE1, PDPN and VEGFR3
Fms-related tyrosine kinase 4, also known as FLT4, is a protein which in humans is encoded by the ''FLT4'' gene.
This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involve ...
, but low levels of PECAM1
Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the ''PECAM1'' gene found on chromosome17q23.3. PECAM-1 plays a key role in removing aged neutrop ...
. Meningeal lymphatic vessels absorb cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
and drain into the deep cervical lymph nodes.[
Several unique attributes differentiate meningeal lymphatic vessels from lymphatic vessels in peripheral organs. Compared to peripheral lymphatic vessels, the meningeal lymphatic network is markedly less complex, with far less tissue coverage and lymphatic branching. Furthermore, meningeal lymphatic vessels are generally smaller than those in the periphery and display a structural homogeneity along the dural sinuses, remaining thinner and mostly unbranched along the superior sagittal sinus while growing larger and more branched along the transverse sinuses.] The meningeal lymphatic vessels are also unique for their scarcity of valves, which prevent back-flow of lymph. While the vessels in the superior parts of the skull were mostly devoid of valves, the larger lymphatic vessels of the basal parts only contain scattered valves.[
]
Development
Development of the dural lymphatic system requires expression of vascular endothelial growth factor C
Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the ''VEGFC'' gene, which is located on chromosom ...
(VEGFC) and its receptor, VEGFR3 (which is the major signaling pathway for lymphatic growth). Meningeal lymphatic vessels increase in diameter when exposed to recombinant VEGFC and completely fail to develop when VEGFC and VEGFD signaling is inhibited during embryogenesis, indicating that meningeal lymphatics share developmental characteristics with peripheral lymphatics. In addition to its role in the development of the dural lymphatics, VEGFR3 signaling is required for lymphatic vessel maintenance in the adult meninges. Mechanical forces and shear stress generated by lymph flow are also required for later stages of meningeal lymphatic vessel formation and maturation.
Physiological functions
Like peripheral lymphatic vessels, the meningeal lymphatics serve both the tissue drainage and immune cell trafficking functions of the lymphatic system. Multiphoton live imaging experiments performed on anesthetized mice have demonstrated that the meningeal lymphatics are capable of draining fluorescent dyes injected intracisternally into the CSF, indicating that the meningeal lymphatics are capable of draining fluid from their surrounding environment. Histological analysis revealed that the meningeal lymphatics constitutively contain T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
, B cells
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
, and MHC class II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial ce ...
-expressing myeloid
Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...
cells, demonstrating that meningeal lymphatic vessels are capable of carrying immune cells.
Furthermore, tracing the outflow of compounds injected into the brain parenchyma have indicated that meningeal lymphatics function downstream of the glymphatic system. Genetically engineered mice which lack the meningeal lymphatic vessels demonstrated attenuated clearance of macromolecules from the brain. The uptake of tracers from the brain into deep cervical lymph nodes was completely abrogated. However, brain interstitial fluid pressure and water content were unaffected. These data suggested that meningeal lymphatic vessels are important for the clearance of macromolecules from the brain parenchyma, but in physiological settings the brain can compensate in solute clearance.
Meningeal lymphatic ablation experiments performed on mice suggests other implications of dysfunctional meningeal lymphatic drainage; an impairment in fear memory and hippocampal-amygdala neuronal circuitry was observed in mice with impaired meningeal lymphatic vessel function. Similar deficits in spatial learning and memory were observed in mice with lymphatic ligation, indicating that the effect is a result of impaired meningeal lymphatic drainage.
Role in disease
The role that the meningeal lymphatics play in diseases of the nervous system is an area of active research, particularly for neurological disorders in which immunity is a fundamental player, such as multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(AD), amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
, Hennekam syndrome
Hennekam syndrome also known as intestinal lymphagiectasia–lymphedema–mental retardation syndrome, is an autosomal recessive disorder consisting of intestinal lymphangiectasia, facial anomalies, peripheral lymphedema, and mild to moderate le ...
, and Prader-Willi syndrome. Impaired clearance of ISF waste has been associated with accelerated accumulation of toxic amyloid beta
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
, the main component of amyloid plaques in AD.
Significance
The paper by Jonathan Kipnis and his postdoctoral fellow Antoine Louveau was published in 2015 and by November 2022, this paper had been cited 3300 times.
The discovery of meningeal lymphatic vessels has attracted attention from many sources, and was touted as a scientific breakthrough in lists such as ''Scientific American
''Scientific American'', informally abbreviated ''SciAm'' or sometimes ''SA'', is an American popular science magazine. Many famous scientists, including Albert Einstein and Nikola Tesla, have contributed articles to it. In print since 1845, it i ...
''s "Top 10 Science Stories of 2015", ''Science Magazine
''Science'', also widely referred to as ''Science Magazine'', is the peer-reviewed academic journal of the American Association for the Advancement of Science (AAAS) and one of the world's top academic journals.
It was first published in 1880, ...
''s "Breakthrough of the Year", Huffington Post's "Eight Fascinating Things We Learned About the Mind in 2015" and the National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
's director Francis Collins's year end review. In 2017, ''Business Insider
''Insider'', previously named ''Business Insider'' (''BI''), is an American financial and business news website founded in 2007. Since 2015, a majority stake in ''Business Insider''s parent company Insider Inc. has been owned by the German publ ...
'' highlighted this as the biggest discovery ever made in Virginia. In 2019, the history of the brain lymphatic system was narrated by Stefano Sandrone
Stefano Sandrone (1988) is an Italian neuroscientist and a Senior Teaching Fellow at Imperial College London.
Life and works
Stefano Sandrone was born in Canelli, Italy, on the 1st of February 1988, and obtained a Ph.D. in Neuroscience at King†...
et al in ''Nature Medicine
''Nature Medicine'' is a monthly Peer review, peer-reviewed medical journal published by Nature Portfolio covering all aspects of medicine. It was established in 1995. The journal seeks to publish research papers that "demonstrate novel insight int ...
''.
References
{{reflist
Lymphatic system
Central nervous system