Bridging barriers: a comparative look at the blood–brain barrier across organisms

O'Brown, Natasha M; Pfau, Sarah J.; Gu, Chenghua

doi:10.1101/gad.309823.117

Cited by 198 publications

(152 citation statements)

References 150 publications

(205 reference statements)

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“…Therefore, a model with the ability to incorporate physiologically relevant shear stresses is essential to effectively capture biologically relevant transport across any barrier in direct contact with the bloodstream. Additional limitations of existing models to probe human brain permeability include the use of rodent brain endothelial cells, which do not exhibit the same anatomical and molecular complexities as their human counterparts . Alternatively, while the use of primary human brain endothelial cells may have significant advantages, these cells can be difficult to acquire, variable in nature, and challenging to culture and maintain, especially in a microfluidic environment …”

Section: Introductionmentioning

confidence: 99%

“…Additional limitations of existing models to probe human brain permeability include the use of rodent brain endothelial cells, 36,40 which do not exhibit the same anatomical and molecular complexities as their human counterparts. 48,49 Alternatively, while the use of primary human brain endothelial cells may have significant advantages, 37,50 these cells can be difficult to acquire, variable in nature, and challenging to culture and maintain, especially in a microfluidic environment. 51 Herein, we report the development of a microfluidic human BBB model (μHuB) with the ability to directly monitor both the barrier and associated transport in the presence of physiologically relevant shear conditions.…”

Section: Introductionmentioning

confidence: 99%

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A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

Brown

Nowak

Bayles

et al. 2019

Bioengineering & Transla Med

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Microfluidic cellular models, commonly referred to as “organs‐on‐chips,” continue to advance the field of bioengineering via the development of accurate and higher throughput models, captivating the essence of living human organs. This class of models can mimic key in vivo features, including shear stresses and cellular architectures, in ways that cannot be realized by traditional two‐dimensional in vitro models. Despite such progress, current organ‐on‐a‐chip models are often overly complex, require highly specialized setups and equipment, and lack the ability to easily ascertain temporal and spatial differences in the transport kinetics of compounds translocating across cellular barriers. To address this challenge, we report the development of a three‐dimensional human blood brain barrier (BBB) microfluidic model (μHuB) using human cerebral microvascular endothelial cells (hCMEC/D3) and primary human astrocytes within a commercially available microfluidic platform. Within μHuB, hCMEC/D3 monolayers withstood physiologically relevant shear stresses (2.73 dyn/cm 2 ) over a period of 24 hr and formed a complete inner lumen, resembling in vivo blood capillaries. Monolayers within μHuB expressed phenotypical tight junction markers (Claudin‐5 and ZO‐1), which increased expression after the presence of hemodynamic‐like shear stress. Negligible cell injury was observed when the monolayers were cultured statically, conditioned to shear stress, and subjected to nonfluorescent dextran (70 kDa) transport studies. μHuB experienced size‐selective permeability of 10 and 70 kDa dextrans similar to other BBB models. However, with the ability to probe temporal and spatial evolution of solute distribution, μHuBs possess the ability to capture the true variability in permeability across a cellular monolayer over time and allow for evaluation of the full breadth of permeabilities that would otherwise be lost using traditional end‐point sampling techniques. Overall, the μHuB platform provides a simplified, easy‐to‐use model to further investigate the complexities of the human BBB in real‐time and can be readily adapted to incorporate additional cell types of the neurovascular unit and beyond.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

Brown

Nowak

Bayles

et al. 2019

Bioengineering & Transla Med

View full text Add to dashboard Cite

show abstract

“…Other cell types also contribute to the characteristics of barrier endothelial cells, including neurons, pericytes, vascular smooth muscle cells (VSMCs), microglia and oligodendrocytes (Broux et al 2015;Keaney and Campbell 2015;O'Brown et al 2018;Miyamoto et al 2014). In addition, one study suggested that neurons have predominant effects on the acquisition of barrier phenotypes by vascular endothelial cells (Tontsch and Bauer 1991).…”

Section: Neural-endothelial Crosstalkmentioning

confidence: 99%

Neural activity regulates autoimmune diseases through the gateway reflex

Štofková

Murakami

2019

Bioelectron Med

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The brain, spinal cord and retina are protected from blood-borne compounds by the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB) and blood-retina barrier (BRB) respectively, which create a physical interface that tightly controls molecular and cellular transport. The mechanical and functional integrity of these unique structures between blood vessels and nervous tissues is critical for maintaining organ homeostasis. To preserve the stability of these barriers, interplay between constituent barrier cells, such as vascular endothelial cells, pericytes, glial cells and neurons, is required. When any of these cells are defective, the barrier can fail, allowing blood-borne compounds to encroach neural tissues and cause neuropathologies. Autoimmune diseases of the central nervous system (CNS) and retina are characterized by barrier disruption and the infiltration of activated immune cells. Here we review our recent findings on the role of neural activity in the regulation of these barriers at the vascular endothelial cell level in the promotion of or protection against the development of autoimmune diseases. We suggest nervous system reflexes, which we named gateway reflexes, are fundamentally involved in these diseases. Although their reflex arcs are not completely understood, we identified the activation of specific sensory neurons or receptor cells to which barrier endothelial cells respond as effectors that regulate gateways for immune cells to enter the nervous tissue. We explain this novel mechanism and describe its role in neuroinflammatory conditions, including models of multiple sclerosis and posterior autoimmune uveitis.

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“…DY131 and TG-003 are both reported to be brain penetrant in mice (9,14,15), so we tested these drugs individually and in combination using a zebrafish intracranial xenograft model (Figure 7A). The zebrafish BBB forms at ~3 days postfertilization (dpf) and is functionally similar to that of higher organisms (43,44). We modified published intracranial xenograft procedures (Figure 7B, (45,46)), injecting labeled 42MGBA-TMZres cells into 1.5 dpf zebrafish embryos.…”

Section: Combination Treatment With Tg-003 and Dy131 Inhibits The Gromentioning

confidence: 99%

Estrogen-related receptor beta activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma

Tiek

Khatib

Trepicchio

et al. 2019

Preprint

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Glioblastoma (GBM; grade 4 glioma) is a highly aggressive and incurable tumor. GBM has recently been characterized as highly dependent on alternative splicing, a critical driver of tumor heterogeneity and plasticity. Estrogen-related receptor beta (ERRβ, ESRRB, NR3B2) is an orphan nuclear receptor expressed in the brain, where alternative splicing of the 3' end of the pre-mRNA leads to the production of three validated ERRβ protein products -ERRβ short form (ERRβsf), ERRβ2, and ERRβ exon 10-deleted (ERRβ-∆10). Our prior studies have shown the ERRβ2 isoform to play a role in G2/M cell cycle arrest and induction of apoptosis, in contrast to the function of the shorter ERRβsf isoform in senescence and G1 cell cycle arrest. In this study, we sought to better define the role of the pro-apoptotic ERRβ2 isoform in GBM. We show that the ERRβ2 isoform is located in the nucleus, but also the cytoplasm. ERRβ2 suppresses GBM cell migration, interacts with the actin nucleation-promoting factor cortactin, and an ERRβ agonist is able to remodel the actin cytoskeleton and similarly suppress GBM cell migration. We further show that inhibition of the splicing regulatory cdc2-like kinases (CLKs) in combination with an ERRβ agonist shifts isoform expression in favor of ERRβ2 and potentiates inhibition of growth and migration in GBM cells and intracranial tumors.

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Bridging barriers: a comparative look at the blood–brain barrier across organisms

Cited by 198 publications

References 150 publications

A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

Neural activity regulates autoimmune diseases through the gateway reflex

Estrogen-related receptor beta activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma

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