A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules (original) (raw)
Related papers
Structural and functional features of central nervous system lymphatic vessels
Nature, 2015
One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call f...
Meningeal lymphatic vessels (MLVs) contribute to waste product elimination and immune surveillance in brain tissues. MLVs were identified in the dorsal and caudo-basal regions of the dura mater, where they ensure the clearance of cerebrospinal fluid (CSF). Whether MLVs exist in the complex anterior part of the murine and human skull, and how they connect with the glymphatic system and extracranial lymphatic vasculature remained unclear. Here, we generated three-dimensional (3D) maps of MLV drainage by light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations following fluorescent OVA-A555 tracer injections into the CSF. In humans, we performed real-time magnetic resonance vessel wall imaging (MR-VWI) after systemic gadobutrol injections. We observed a conserved 3D-anatomy of MLVs in mice and humans, and we discovered an extended anterior network around the dural cavernous sinus including multiple capillary beds and exit routes through the foramina of emissa...
Conserved meningeal lymphatic drainage circuits in mice and humans
Journal of Experimental Medicine
Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune surveillance of brain tissues. Whether MLVs exist in the anterior part of the murine and human skull and how they connect with the glymphatic system and extracranial lymphatics remained unclear. Here, we used light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations after OVA-A555 tracer injection into the cerebrospinal fluid (CSF) and performed real-time vessel-wall (VW) magnetic resonance imaging (VW-MRI) after systemic injection of gadobutrol in patients with neurological pathologies. We observed a conserved three-dimensional anatomy of MLVs in mice and humans that aligned with dural venous sinuses but not with nasal CSF outflow, and we discovered an extended anterior MLV network around the cavernous sinus, with exit routes through the foramina of emissary veins. VW-MRI may provide a diagnostic ...
Dynamic properties of lymphatic pathways for the absorption of cerebrospinal fluid
Acta Neuropathologica, 1997
To study the dynamics of the outflow of cerebrospinal fluid (CSF) into the cervical lymphatic system, X-ray contrast medium or Indian ink was infused into the cisterna magna of rats at moderately increased intracranial pressure (40-50 mm Hg). In the first series of experiments, while the contrast medium was being infused, the animal's head was examined using X-ray-microscopy (× 4-20 direct magnification radiography) and conventional radiography. Within the first minutes of infusion, the flow of CSF was directed from the posterior fossa to the olfactory bulb. Reaching the cribriform plate approximately 7 min after starting the infusion, the contrast medium leaked into the nasal cavities. Some minutes later, it opacified the subarachnoid space (SAS) of the optic nerve, the perilymphatic space of the inner ear, the cortical SAS, and the transverse sinuses. Leakage from the optic nerve SAS into the orbit was seen after 30 min infusion. In the second series of experiments, the Indian ink was infused after microsurgical exposure of the cervical lymph vessels. During the infusion the cervical lymph ducts were observed microscopically (× 40 magnification). Single dye particles draining through the cervical lymph ducts appeared 20 min after the start of cisternal infusion. Their transport was rapid, and dependent on the respiratory cycle: during inspiration the particles moved at a speed of 10-20 mm/s, during expiration the movement stopped. Thus, rapid kinetics are demonstrated for the outflow of CSF and particles from the SAS into the cervical lymphatics.
In most tissues and organs, the lymphatic circulation is responsible for the removal of interstitial protein and fluid but the parenchyma of the brain and spinal cord is devoid of lymphatic vessels. On the other hand, the literature is filled with qualitative and quantitative evidence supporting a lymphatic function in cerebrospinal fluid (CSF) absorption. The experimental data seems to warrant a re-examination of CSF dynamics and consideration of a new conceptual foundation on which to base our understanding of disorders of the CSF system. The objective of this paper is to review the key studies pertaining to the role of the lymphatic system in CSF absorption.
Structural and functional features of central nervous system lymphatics
-privileged organ, largely because of the lack of classical lymphatic drainage system. However, immune surveillance of the CNS and the presence of meningeal T cells are now well established, although the mechanisms governing immune-cell circulation through the CNS have remained poorly understood. Here we report that in searching for T-cell gateways into and out of the brain meninges, we discovered conduits for immune cells in vessel-like structures immediately adjacent to the dural sinuses. These structures expressed the endothelial cell marker CD31, and exhibited all of the molecular hallmarks of lymphatic endothelial cells. Using intravital multiphoton microscopy we demonstrated that meningeal lymphatic vessels drain cerebrospinal fluid (CSF) and immune cells from meningeal spaces and that their obstruction results in a significant increase in the numbers of meningeal T cells. The unique location of these meningeal lymphatic vessels adjacent to the dural sinuses may have impeded their discovery up to now, thereby contributing to the long-held concept that the immune privilege of the brain is attributable to the absence of lymphatic vessels. This discovery of lymphatic drainage of immune cells and molecules from the meninges via bona-fide lymphatic vessels calls for a reassessment of basic assumptions in neuroimmunology and may shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune-system dysfunction.
Frontiers in Physiology
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 subsets 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.
Anatomy and Embryology, 2006
Development of cerebrospinal fluid absorption sites in the pig and rat: connections between the subarachnoid space and lymphatic vessels in the olfactory turbinates Abstract The textbook view that cerebrospinal fluid (CSF) absorption occurs mainly through the arachnoid granulations and villi is being challenged by quantitative and qualitative studies that support a major role for the lymphatic circulation in CSF transport. There are many potential sites at which lymphatics may gain access to CSF but the primary pathway involves the movement of CSF through the cribriform plate foramina in association with the olfactory nerves. Lymphatics encircle the nerve trunks on the extracranial surface of the cribriform plate and absorb CSF. However, the time during development in which the CSF compartment and extracranial lymphatic vessels connect anatomically is unclear. In this report, CSF-lymphatic connections were investigated using the silastic material Microfil and a soluble Evan's blue-protein complex in two species; one in which significant CSF synthesis by the choroid plexus begins before birth (pigs) and one in which CSF secretion is markedly up regulated within the first weeks after birth (rats). We examined a total of 46 pig fetuses at embryonic (E) day E80-81, E92, E101, E110 (birth at 114 days). In rats, we investigated a total of 115 animals at E21 (birth at 21 days), postnatal (P) day P1-P9, P12, P13, P15, P22, and adults. In pigs, CSF-lymphatic connections were observed in the prenatal period as early as E92. Before this time (E80-81 fetuses) CSF-lymphatic connections did not appear to exist. In rats, these associations were not obvious until about a week after birth. These data suggest that the ability of extracranial lymphatic vessels to absorb CSF develops around the time that significant volumes of CSF are being produced by the choroid plexus and further support an important role for lymphatic vessels in CSF transport.
Frontiers in Neurology, 2021
Background: Recent emerging evidence has highlighted the potential critical role of cerebrospinal fluid (CSF) in cerebral waste clearance and immunomodulation. It is already very well-established that the central nervous system (CNS) is completely submerged in CSF on a macro-level; but to what extent is this true on a micro-level? Specifically, within the peri-neural and peri-vascular spaces within the CNS parenchyma. Therefore, the objective of this study was to use magnetic resonance imaging (MRI) to simultaneously map the presence of CSF within all peri-neural (cranial and spinal nerves) and peri-vascular spaces in vivo in humans. Four MRI protocols each with five participants were used to image the CSF in the brain and spinal cord. Our findings indicated that all CNS neuro- and vascular-communication channels are surrounded with CSF. In other words, all peri-neural spaces surrounding the cranial and spinal nerves as well as all peri-vascular spaces surrounding MRI-visible vascul...