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An inverted blood-brain barrier model that permits interactions between glia and inflammatory stimuli.

ABSTRACT: The blood-brain barrier (BBB) is increasingly being recognized as a site of special scientific importance. Numerous models of the BBB have been constructed over the past years with increasingly mechanistic studies of fundamental questions of cell biology and neuroimmunology. However, there has been a limiting factor of not being able to perform real-time studies of BBB function utilizing 3D models. Equally, real-time models have been limited mainly to 2D models comprised solely of endothelial cells (ECs). To measure changes in the electrical resistance across a BBB model, when adding inflammatory or stem cells which will interact with co-cultured glial cells has, to date, been beyond the capabilities of models. We have cultured an inverted BBB model with ECs on electrodes which are on the lower surface of xCELLigence Cell Invasion Migration plates. Glial cells were cultured in the basal well with foot processes extending through the filters to make contact with the ECs. SIV-infected macrophages decreased electrical resistance of the EC monolayer when added to the "parenchymal" face of the model. We present a novel inverted blood-brain barrier model that allow real time analyses of endothelial cell adhesion during modeled neuroinflammation.

SUBMITTER: Sansing HA

PROVIDER: S-EPMC3348346 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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An inverted blood-brain barrier model that permits interactions between glia and inflammatory stimuli.

Sansing Hope A HA Renner Nicole A NA MacLean Andrew G AG

Journal of neuroscience methods 20120406 1

The blood-brain barrier (BBB) is increasingly being recognized as a site of special scientific importance. Numerous models of the BBB have been constructed over the past years with increasingly mechanistic studies of fundamental questions of cell biology and neuroimmunology. However, there has been a limiting factor of not being able to perform real-time studies of BBB function utilizing 3D models. Equally, real-time models have been limited mainly to 2D models comprised solely of endothelial ce ...[more]

PMID: 22484463

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Project description:The blood-brain barrier (BBB) is an evolutionary conserved tissue interface that possesses potent chemical protection properties functioning to strictly modulate the central nervous system (CNS) microenvironment. These same properties, including tight cellular junctions and efflux transporters, also limit access of CNS-active pharmaceuticals. For this reason, understanding the molecular mechanisms that regulate BBB chemical protection is of great biomedical interest. The BBB of Drosophila consists of two surface glia layers that completely surround the brain. This tissue interface contains both “tight” cellular junctions (termed septate junctions) and drug efflux transporters; thus, the Drosophila BBB can potentially serve as a model for understanding complex regulation of BBB physiology. In this study, we show reciprocal compensatory responses following disruption of critical BBB genes: deletion of the septate junction regulator Moody causes increased drug efflux and up-regulation of the P-glycoprotein ortholog Mdr65; conversely, disruption of Mdr65 expression causes increased septate junction tightness and up-regulation of Moody. We reveal these homeostatic interactions with physiologic observations, gene expression data, and anatomical images of the BBB surface. Whole brain microarray data point to responses that are consistent with our physiologic observations and these responses are likely localized to the BBB. To our knowledge, this is the first observation of a reciprocal compensatory interaction at a tissue barrier. Furthermore, this study paves the way for future studies elucidating the direct pathways that link GPCR signaling and drug transporter regulation at the BBB. The main comparisons are between WT_new, C17 (Moody null), and PMdr65 (Mdr65 null). Since WT_new were processed on a different day than C17 and PMdr65, we also included another WT sample (WT_old) to control for genes that change depending on batch effects. Since the mutants are also in a different genetic background than WT, we also included a control that is in a similar background (UAS_control).

Project description:Focused ultrasound (FUS) in combination with systemically injected microbubbles can be used to non-invasively open the blood-brain barrier (BBB) in targeted regions for a variety of therapeutic applications. Over the past two decades, preclinical research into the safety and efficacy of FUS-induced BBB opening has proven this technique to be transient and efficacious, propelling FUS-induced BBB opening into several clinical trials in recent years. However, as clinical trials further progress, the neuroinflammatory response to FUS-induced BBB opening needs to be better understood. In this study, we provide further insight into the relationship of microbubble cavitation and the resulting innate immune response to FUS-induced BBB opening. By keeping ultrasound parameters fixed (i.e. frequency, pressure, pulse length, etc.), three groups of mice were sonicated using a real-time cavitation controller until a target cavitation dose was reached (1 x 107 V2•s, 5 x 107 V2•s, 1 x 108 V2•s). The change in relative gene expression of the mouse inflammatory cytokines and receptors were evaluated at three different time-points (6 h, 24 h, and 72 h) after FUS. At both 6 and 24 h time-points, significant changes in relative gene expression of inflammatory cytokines and receptors were observed across all cavitation groups. However, the degree of changes in relative expression levels and the number of genes with significant changes in expression varied across the cavitation groups. Groups with a higher cavitation dose exhibited both greater changes in relative expression levels and greater number of significant changes. By 72 h post-opening, the gene expression levels returned to baseline in all cavitation dose groups, signifying a transient inflammatory response to FUS-induced BBB opening at the targeted cavitation dose levels. Furthermore, the real-time cavitation controller was able to produce consistent and significantly different BBB permeability enhancement volumes across the three different cavitation dose groups. These results indicate that cavitation monitoring and controlling during FUS-induced BBB opening can be used to potentially modulate or limit the degree of neuroinflammation, further emphasizing the importance of implementing cavitation controllers as FUS-induced BBB opening is translated into the clinic.

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An inverted blood-brain barrier model that permits interactions between glia and inflammatory stimuli.

Publications

An inverted blood-brain barrier model that permits interactions between glia and inflammatory stimuli.

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