Fluids and Barriers of the CNS

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ISSN / EISSN : 20458118 / 20458118
Current Publisher: Springer Science and Business Media LLC (10.1186)
Total articles ≅ 433
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Misaki Yamashita, Hiromasa Aoki, Tadahiro Hashita, Takahiro Iwao, Tamihide Matsunaga
Fluids and Barriers of the CNS, Volume 17, pp 1-12; doi:10.1186/s12987-020-00197-1

Abstract:
The blood–brain barrier (BBB) plays an important role as a biological barrier by regulating molecular transport between circulating blood and the brain parenchyma. In drug development, the accurate evaluation of BBB permeability is essential to predict not only the efficacy but also the safety of drugs. Recently, brain microvascular endothelial-like cells derived from human induced pluripotent stem cells (iPSCs) have attracted much attention. However, the differentiation protocol has not been optimized, and the enhancement of iPSC-derived brain microvascular endothelial-like cells (iBMELCs) function is required to develop highly functional BBB models for pharmaceutical research. Thus, we attempted to improve the functions of differentiated iBMELCs and develop a versatile BBB model by modulating TGF-β signaling pathway without implementing complex techniques such as co-culture systems. iPSCs were differentiated into iBMELCs, and TGF-β inhibitor was used in the late stage of differentiation. To investigate the effect of TGF-β on freezing–thawing, iBMELCs were frozen for 60–90 min or 1 month. The barrier integrity of iBMELCs was evaluated by transendothelial electrical resistance (TEER) values and permeability of Lucifer yellow. Characterization of iBMELCs was conducted by RT-qPCR, immunofluorescence analysis, vascular tube formation assay, and acetylated LDL uptake assay. Functions of efflux transporters were defined by intracellular accumulation of the substrates. When we added a TGF-β inhibitor during iBMELCs differentiation, expression of the vascular endothelial cell marker was increased and blood vessel-like structure formation was enhanced. Furthermore, TEER values were remarkably increased in three iPSC lines. Additionally, it was revealed that TGF-β pathway inhibition suppressed the damage caused by the freezing–thawing of iBMELCs. We succeeded in significantly enhancing the function and endothelial characteristics of iBMELCs by adding a small molecular compound, a TGF-β inhibitor. Moreover, the iBMELCs could maintain high barrier function even after freezing–thawing. Taken together, these results suggest that TGF-β pathway inhibition may be useful for developing iPSC-derived in vitro BBB models for further pharmaceutical research.
Peter Solár, Alemeh Zamani, Lucie Kubíčková, Petr Dubový, Marek Joukal
Fluids and Barriers of the CNS, Volume 17, pp 1-29; doi:10.1186/s12987-020-00196-2

Abstract:
The choroid plexus (CP) forming the blood–cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research.
Karen Brastad Evensen, Per Kristian Eide
Fluids and Barriers of the CNS, Volume 17, pp 34-33; doi:10.1186/s12987-020-00195-3

Abstract:
Sixty years have passed since neurosurgeon Nils Lundberg presented his thesis about intracranial pressure (ICP) monitoring, which represents a milestone for its clinical introduction. Monitoring of ICP has since become a clinical routine worldwide, and today represents a cornerstone in surveillance of patients with acute brain injury or disease, and a diagnostic of individuals with chronic neurological disease. There is, however, controversy regarding indications, clinical usefulness and the clinical role of the various ICP scores. In this paper, we critically review limitations and weaknesses with the current ICP measurement approaches for invasive, less invasive and non-invasive ICP monitoring. While risk related to the invasiveness of ICP monitoring is extensively covered in the literature, we highlight other limitations in current ICP measurement technologies, including limited ICP source signal quality control, shifts and drifts in zero pressure reference level, affecting mean ICP scores and mean ICP-derived indices. Control of the quality of the ICP source signal is particularly important for non-invasive and less invasive ICP measurements. We conclude that we need more focus on mitigation of the current limitations of today's ICP modalities if we are to improve the clinical utility of ICP monitoring.
Grant Alexander Bateman, Swee Leong Yap, Gopinath Musuwadi Subramanian, Alexander Robert Bateman
Fluids and Barriers of the CNS, Volume 17, pp 1-12; doi:10.1186/s12987-020-00194-4

Abstract:
Symptomatic or active hydrocephalus in children is linked to an elevation in intracranial pressure (ICP), which is likely to be multifactorial in origin. The CSF outflow resistance, venous sinus resistance and total cerebral blood flow are likely factors in the ICP elevation. The purpose of this paper is to define the incidence, site and significance of venous sinus stenosis and/or cerebral hyperemia in a cohort of children diagnosed with hydrocephalus at a tertiary referral hospital. The imaging database was reviewed over a 10 year period and the index MRI of all children between the ages of 4 months and 15 years, who were diagnosed with treatment naive hydrocephalus of any type (excluding secondary to tumor) and had magnetic resonance venography (MRV) and flow quantification were selected. Patients were compared with children undergoing an MRI with MRV and flow quantification who were subsequently shown to have no abnormality. The cross-sectional area and circumference of the sinuses were measured at 4 levels. The hydraulic and effective diameters were calculated. An area stenosis of 65% or greater was deemed significant. A total cerebral blood flow greater than two standard deviations above the mean for controls was taken to be abnormal. There were a total of 55 children with hydrocephalus compared to 118 age matched control MRV’s and 35 control flow quantification studies. A high grade stenosis occurred in 56% of patients but in none of the controls (p < 0.0001). The commonest site of narrowing was in the distal sigmoid sinus. Cerebral hyperemia occurred in 13% of patients but did not occur in the controls. The elevation in ICP in symptomatic hydrocephalus is multifactorial. Both high grade venous stenosis and cerebral hyperemia are common in childhood hydrocephalus. High grade stenosis was noted to be a risk factor for conservative management failure. Hyperemia was a good prognostic indicator.
Carolin J. Curtaz, Constanze Schmitt, Saskia-Laureen Herbert, Jonas Feldheim, Nicolas Schlegel, Fabien Gosselet, Carsten Hagemann, Norbert Roewer, Patrick Meybohm, Achim Wöckel, et al.
Fluids and Barriers of the CNS, Volume 17, pp 31-12; doi:10.1186/s12987-020-00192-6

Abstract:
The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). We adapted and validated the CD34+ cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. We demonstrate that the CD34+ cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with cerebral metastases may affect the integrity of the BBB in vitro, associated with elevated concentrations of specific cytokines such as CX3CL1 and CXCL13.
Michael J. Workman, Clive N Svendsen
Fluids and Barriers of the CNS, Volume 17, pp 1-10; doi:10.1186/s12987-020-00191-7

Abstract:
The blood–brain barrier (BBB) is a critical component of the central nervous system that protects neurons and other cells of the brain parenchyma from potentially harmful substances found in peripheral circulation. Gaining a thorough understanding of the development and function of the human BBB has been hindered by a lack of relevant models given significant species differences and limited access to in vivo tissue. However, advances in induced pluripotent stem cell (iPSC) and organ-chip technologies now allow us to improve our knowledge of the human BBB in both health and disease. This review focuses on the recent progress in modeling the BBB in vitro using human iPSCs.
C. Goldeman, B. Ozgür, B. Brodin
Fluids and Barriers of the CNS, Volume 17, pp 1-12; doi:10.1186/s12987-020-00193-5

Abstract:
The complexity of the neurovascular unit (NVU) poses a challenge in the investigations of drug transport across the blood–brain barrier (BBB) and the function of the brain capillary endothelium. Several in vitro models of the brain capillary endothelium have been developed. In vitro culture of primary endothelial cells has, however, been reported to alter the expression levels of various brain endothelial proteins. Only a limited number of studies have addressed this in detail. The aim of the present study was to investigate mRNA levels of selected BBB transporters and markers in in vitro models of the BBB based on bovine primary endothelial cells and compare these to the levels estimated in freshly isolated bovine brain capillaries. Brain capillaries were isolated from bovine cerebral cortex grey matter. Capillaries were seeded in culture flasks and endothelial cells were obtained using a brief trypsinization. They were seeded onto permeable supports and cultured in mono-, non-contact- or contact co-culture with/without primary rat astrocytes. mRNA-expression levels of the selected BBB markers and transporters were evaluated using qPCR and monolayer integrity of resulting monolayers was evaluated by measuring the transendothelial electrical resistance (TEER). The capillary mRNA transcript profile indicated low expression of ABCC1 and CLDN1. The mRNA expression levels of TPA, OCLN, ABCB1, SLC2A1, SLC16A1 and SLC7A5 were significantly decreased in all culture configurations compared to freshly isolated bovine brain capillaries. ALP, VWF, ABCC1 and ABCC4 were upregulated during culture, while the mRNA expression levels of F11R, TJP1, CLDN5, CLDN1 and ABCG2 were found to be unaltered. The mRNA expression levels of VWF, ALP, ABCB1 and ABCC1 were affected by the presence of rat astrocytes. The endothelial mRNA transcript profile in bovine capillaries obtained in this study correlated nicely with profiles reported in mice and humans. Cultured endothelial cells drastically downregulated the mRNA expression of the investigated SLC transporters but maintained expression of efflux transporter and junctional protein mRNA, implying that the bovine in vitro BBB models may serve well to investigate basic barrier biology and in vivo permeation of passively permeating compounds and efflux transporter substrates but may be less well suited for investigations of SLC-mediated transport.
James R Connor, Kari Duck, Stephanie Patton, Ian A. Simpson, Lynn Marie Trotti, Richard Allen, Christopher J. Earley, David Rye
Fluids and Barriers of the CNS, Volume 17, pp 1-4; doi:10.1186/s12987-020-00190-8

Abstract:
Iron is crucial for proper functioning of all organs including the brain. Deficiencies and excess of iron are common and contribute to substantial morbidity and mortality. Whereas iron’s involvement in erythropoiesis drives clinical practice, the guidelines informing interventional strategies for iron repletion in neurological disorders are poorly defined. The objective of this study was to determine if peripheral iron status is communicated to the brain. We used a bi-chamber cell culture model of the blood–brain-barrier to determine transcytosis of iron delivered by transferrin as a metric of iron transport. In the apical chamber (representative of the blood) we placed transferrin complexed with iron59 and in the basal chamber (representative of the brain) we placed human cerebrospinal fluid. Cerebrospinal fluid (CSF) samples (N = 24) were collected via lumbar puncture. The integrity of the tight junctions were monitored throughout the experiments using RITC-Dextran. We demonstrate that iron transport correlates positively with plasma hemoglobin concentrations but not serum ferritin levels. The clinical ramifications of these findings are several- fold. They suggest that erythropoietic demands for iron take precedence over brain requirements, and that the metric traditionally considered to be the most specific test reflecting total body iron stores and relied upon to inform treatment decisions–i.e., serum ferritin–may not be the preferred peripheral indicator when attempting to promote brain iron uptake. The future direction of this line of investigation is to identify the factor(s) in the CSF that influence iron transport at the level of the BBB.
Vegard Vinje, Anders Eklund, Kent-Andre Mardal, Marie E. Rognes, Karen-Helene Støverud
Fluids and Barriers of the CNS, Volume 17, pp 29-19; doi:10.1186/s12987-020-00189-1

Abstract:
Infusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models. We used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters. At baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/(mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route. The relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.
Ofri Bar, Sivan Gelb, Kian Atamny, Shira Anzi, Ayal Ben-Zvi
Fluids and Barriers of the CNS, Volume 17, pp 1-12; doi:10.1186/s12987-020-00188-2

Abstract:
Several secreted factors have been identified as drivers of cerebral vasculature development and inducers of blood–brain barrier (BBB) differentiation. Vascular endothelial growth factor A (VEGF-A) is central for driving cerebral angiogenesis and Wnt family factors (Wnt7a, Wnt7b and norrin) are central for induction and maintenance of barrier properties. Expressed by developing neural tissue (neuron and glia progenitors), they influence the formation of central nervous system (CNS) vascular networks. Another type of factors are tissue-specific paracrine factors produced by endothelial cells (ECs), also known as ‘angiocrine’ factors, that provide instructive signals to regulate homeostatic and regenerative processes. Very little is known about CNS angiocrine factors and their role in BBB development. Angiomodulin (AGM) was reported to be expressed by developing vasculature and by pathological tumor vasculature. Here we investigated AGM in the developing CNS and its function as a potential BBB inducer. We analyzed microarray data to identify potential angiocrine factors specifically expressed at early stages of barrier formation. We then tested AGM expression with immunofluorescence and real-time PCR in various organs during development, post-natal and in adults. Permeability induction with recombinant proteins (Miles assay) was used to test potential interaction of AGM with VEGF-A. Several angiocrine factors are differentially expressed by CNS ECs and AGM is a prominent CNS-specific angiocrine candidate. Contrary to previous reports, we found that AGM protein expression is specific to developing CNS endothelium and not to highly angiogenic developing vasculature in general. In skin vasculature we found that AGM antagonizes VEGF-A-induced vascular hyperpermeability. Finally, CNS AGM expression is not specific to BBB vasculature and AGM is highly expressed in non-BBB choroid-plexus vasculature. We propose AGM as a developmental CNS vascular-specific marker. AGM is not a pan-endothelial marker, nor a general marker for developing angiogenic vasculature. Thus, AGM induction in the developing CNS might be distinct from its induction in pathology. While AGM is able to antagonize VEGF-A-induced vascular hyperpermeability in the skin, its high expression levels in non-BBB CNS vasculature does not support its potential role as a BBB inducer. Further investigation including loss-of-function approaches might elucidate AGM function in the developing CNS.
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