The Cell Biology of the Blood-Brain Barrier

Rubin, Lee L.; Staddon, James M.

doi:10.1146/annurev.neuro.22.1.11

Cited by 913 publications

(594 citation statements)

References 86 publications

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“…The BBB cells containing tight junctions serve to restrict and control the movement of substances between the systemic circulation and brain extracellular fluid and are characterized by a high TEER and low permeability [8,11,14,18,49,59]. BBB disruption leads to extravasation of plasma proteins into the brain through transcellular and paracellular routes [34,54,63]. Our understanding of the mechanisms that lead to the disruption of the BBB is limited.…”

Section: Discussionmentioning

confidence: 99%

“…The disruption of the bloodbrain barrier integrity has been shown to occur in many neurological disorders such as Alzheimer's disease, stroke and HIV-1 encephalopathy [34,54,63] but the mechanisms involved in BBB disruption remain incompletely understood. A major limiting factor is the lack of reliable models of the human blood-brain barrier.…”

Section: Introductionmentioning

confidence: 99%

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Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells

et al. 2007

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The blood-brain barrier (BBB) is a structural and functional barrier that regulates the passage of molecules into and out of the brain to maintain the neural microenvironment. We have previously developed the in vitro BBB model with human brain microvascular endothelial cells (HBMEC). However, in vivo HBMEC are shown to interact with astrocytes and also exposed to shear stress through blood flow. In an attempt to develop the BBB model to mimic the in vivo condition we constructed the flow-based in vitro BBB model using HBMEC and human fetal astrocytes (HFA). We also examined the effect of astrocyte conditioned medium (ACM) in lieu of HFA to study the role of secreted factor(s) on the BBB properties. The tightness of HBMEC monolayer was assessed by the permeability of dextran and propidium iodide as well as by measuring the transendothelial electrical resistance (TEER). We showed that the HBMEC permeability was reduced and TEER was increased by non-contact, co-cultivation with HFA and ACM. The exposure of HBMEC to shear stress also exhibited decreased permeability. Moreover, HFA/ACM and shear flow exhibited additive effect of decreasing the permeability of HBMEC monolayer. In addition, we showed that the HBMEC expression of ZO-1 (tight junction protein) was increased by co-cultivation with ACM and in response to shear stress. These findings suggest that the non-contact co-cultivation with HFA helps maintain the barrier properties of HBMEC by secreting factor(s) into the medium. Our in vitro flow model system with the cells of human origin should be useful for studying the interactions between endothelial cells, glial cells, and secreted factor(s) as well as the role of shear stress in the barrier property of HBMEC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells

et al. 2007

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“…Immunohistochemical staining showed that the culture system consisted of pure endothelial cells. In vitro models are generally more permeable than the BBB in vivo, but permeability can be decreased by co-culturing the cells with astrocytes (Rubin et al 1991) or by the use of various compounds that cause an elevation of cAMP levels, thereby increasing barrier function (Rubin and Staddon 1999). With these approaches, we were able to obtain relatively high TEER.…”

Section: Discussionmentioning

confidence: 99%

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Vı́gh

Kastin

Liao

et al. 2004

Experimental Brain Research

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Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are two highly selective mu-opiate receptor agonists. We recently demonstrated that EM-1 and EM-2 have a saturable transport system from brain-to-blood in vivo. Since the endothelial cells are the main component of the non-fenestrated microvessels of the blood-brain barrier (BBB), we examined whether these endogenous tetrapeptides have a saturable transport system in cultured cerebral endothelial cells. EM-1 and EM-2 binding and transport were studied in a transwell system in which primary mouse endothelial cells were co-cultured with rat glioma cells. We found that binding of both endomorphins was greater on the basolateral than the apical cell surface. Flux of EM-1 and EM-2 occurred predominantly in the basolateral to apical direction, each showing self-inhibition with an excess of the respective endomorphin. Transport was not influenced by the addition of the Pglycoprotein inhibitor, cyclosporin A. Neither the mu-opiate receptor agonist DAMGO nor the delta-opiate receptor agonist DPDPE had any effect on the transport. Thus, the results show that a saturable transport system for EM-1 and EM-2 occurs at the level of endothelial cells of the BBB, and unlike β-endorphin and morphine, P-glycoprotein is not needed for the brain-to-blood transport. Cross-inhibition of the transport of each endomorphin by the other suggests a shared transport system that is different from mu-or delta-opiate receptors. As endormorphins are mainly produced in the CNS, the presence of the efflux system at the BBB could play an important role in pain modulation and neuroendocrine control.

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“…To this end, it is guarded by the blood-brain barrier that is impermeable for resting lymphocytes or large effector molecules, such as antibodies. 33 Furthermore, neurons fail to express MHC class I or II determinants and thus provide neither a stimulus nor a target for T cells. 34 Microglial cells and astrocytes can express antigen in the context of MHC class I and II molecules, but their function in antigen presentation is ill defined.…”

Section: Discussionmentioning

confidence: 99%

A DNA vaccine expressing tyrosinase-related protein-2 induces T-cell-mediated protection against mouse glioblastoma

et al. 2003

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A mouse glioblastoma cell line, termed GL261, was shown to express high levels of proteins involved in melanin biosynthesis such as the tyrosinase-related protein-2 (TRP-2), which is commonly overexpressed in melanoma cells. Mice injected with GL261 cells developed a CD8 + T-cell response to TRP-2 and a DNA vaccine expressing human (h)TRP-2 induced CD8 + T cells that recognized TRP-2 expressed by GL261 cells indicating that this melanoma-associated antigen may be suited for active immunotherapy of glioblastoma. Mice vaccinated with a DNA vaccine expressing TRP-2 were partially protected against subcutaneous, intravenous, or intracerebral challenge with the glioblastoma cells. Vaccine-induced protection against intracerebral challenge required both CD4 + and CD8 + T cells. Vaccine efficacy was enhanced upon addition of IL-12 as a genetic adjuvant. These results indicate that this well-defined melanoma-associated antigen can induce an adaptive immune response, which limits the intracerebral progression of a glioblastoma.

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The Cell Biology of the Blood-Brain Barrier

Cited by 913 publications

References 86 publications

Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells

Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

A DNA vaccine expressing tyrosinase-related protein-2 induces T-cell-mediated protection against mouse glioblastoma

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