An immunohistochemical study of lymphatic elements in the human brain

Abstract

Almost 150 papers about brain lymphatics have been published in the last 150 years. Recently, the information in these papers has been synthesized into a picture of central nervous system (CNS) “glymphatics,” but the fine structure of lymphatic elements in the human brain based on imaging specific markers of lymphatic endothelium has not been described. We used LYVE1 and PDPN antibodies to visualize lymphatic marker-positive cells (LMPCs) in postmortem human brain samples, meninges, cavernous sinus (cavum trigeminale), and cranial nerves and bolstered our findings with a VEGFR3 antibody. LMPCs were present in the perivascular space, the walls of small and large arteries and veins, the media of large vessels along smooth muscle cell membranes, and the vascular adventitia. Lymphatic marker staining was detected in the pia mater, in the arachnoid, in venous sinuses, and among the layers of the dura mater. There were many LMPCs in the perineurium and endoneurium of cranial nerves. Soluble waste may move from the brain parenchyma via perivascular and paravascular routes to the closest subarachnoid space and then travel along the dura mater and/or cranial nerves. Particulate waste products travel along the laminae of the dura mater toward the jugular fossa, lamina cribrosa, and perineurium of the cranial nerves to enter the cervical lymphatics. CD3-positive T cells appear to be in close proximity to LMPCs in perivascular/perineural spaces throughout the brain. Both immunostaining and qPCR confirmed the presence of adhesion molecules in the CNS known to be involved in T cell migration.

Global cerebrospinal fluid circulation mapping using gold nanoparticle enhanced X-ray microtomography reveals region-specific brain and spinal cord CSF pathways

“…Similar to prior studies, we observed CSF in and around cranial nerves. It has previously been suggested that cranial nerves play a role in CSF outflow to the lymphatic system 15,18,57 , where a recent study of human lymphatic CNS elements found LYVE-1 staining in the endoneurium of the trigeminal nerve and the perineurium of the glossopharyngeal, vagus, and accessory cranial nerves. 57 By comparing small and large CSF solute distribution, we find large CSF solute circulation around the optic nerve as it emerged from the chiasm, into the eye (Figure 7h), compared to small CSF solutes, which were observed within the optic nerve itself (Figure 7h, 7j).…”

Cell Therapy of Stroke: Do the Intra-Arterially Transplanted Mesenchymal Stem Cells Cross the Blood–Brain Barrier?

“…After ischemic brain damage, transmigrating leukocytes—in particular neutrophils—produce matrix metalloproteinases (MMP), for example, MMP-9, which provoke the development of neuroinflammation and aggravate the BBB integrity interruption. Despite the fact that MSCs themselves produce various MMPs, their activity is controlled by the production of the tissue inhibitor of metalloproteinase (TIMP) [ 80 ]. It has been shown that MSCs are capable of inhibiting exogenous MMPs, namely MMP-2 and MMP-9, through TIMP-2 and TIMP-1, respectively [ 81 ].…”

The Role of Lymphatic Marker Prox-1 in Relation to Brain Tumours

“…were discovered about a decade ago [24]. The brain was very long time considered as organ lacking lymph vessels.…”

“…The traditional concept of CSF homeostasis has been challenged by the latest reports when the existence of a network of true lymphatic vessels in the brain meninges was after more than 200 years reconsidered [23]. The meningeal lymphatic vessels (MLV) found within the mouse dura mater were rediscovered in 2015 by two independent groups using novel, specific lymphatic endothelial markers [24]. They declared that the MLV which are located both dorsally and basally beneath the skull have a direct access to the CSF and, under healthy conditions continuously drain both soluble molecules and immune cells from the subarachnoid space into the cervical lymph nodes (CLNs) The most recent study of lymphatic elements in the human brain brought new knowledge, that the fine lymphatic structure was presented in membranes covering the brain, walls of vessels, perivascular spaces and among nerve fibres.…”