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Review
. 2014 Aug;45(8):2514-26.
doi: 10.1161/STROKEAHA.114.005427. Epub 2014 Jun 17.

Cell-culture models of the blood-brain barrier

Yarong He  1 , Yao Yao  1 , Stella E Tsirka  1 , Yu Cao  2
Affiliations
Review

Cell-culture models of the blood-brain barrier

Yarong He et al. Stroke. 2014 Aug.
No abstract available

Keywords: astrocytes; blood-brain barrier; endothelial cells; in vitro; pericytes.

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Figures

Figure 1
Figure 1
Major transporters and receptors in brain microvascular endothelial cells (BMECs). Oxygen, carbon dioxide, and mall lipophilic agents diffuse across blood–brain barrier freely. Glucose transporter (GLUT1), lactate transporter (MCT1), essential amino acid transporters (LAT1 and SLC7A1) are expressed on both luminal and abluminal sides of BMECs, and transport nutrients bidirectionally. Transferrin receptor (TFR) and insulin receptor (IR) are also expressed on both sides of BMECs, and mediate endocytosis of transferrin and insulin, respectively, leading to accumulation of these molecules in BMECs. Multidrug resistance-related protein 1 (MRP1), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) are predominantly expressed on the luminal side of BMECs and regulate drug efflux. excitatory amino acid transporters 1 to 3 (EAAT1–3) and lipoprotein receptor-related protein 1 (LRP1) are solely expressed on the abluminal side of BMECs and remove glutamate and β-amyloid from the brain, respectively. (Na+-K+)ATPase is expressed only on the abluminal side of BMECs, and controls ion homeostasis in the brain.
Figure 2
Figure 2
In vitro blood–brain barrier (BBB) models. A, Brain microvascular endothelial cell (BMEC) monolayer model (left), BMEC–astrocyte coculture models (middle 2), and BMEC–pericyte–astrocyte triple-culture model (right). B, Cone-plate apparatus. α is the cone angle. C, Dynamic in vitro BBB model. D, Cross-section of one hollow fiber.
Figure 3
Figure 3
Microfluidic-based in vitro blood–brain barrier (BBB) models. A, Microfluidic BBB (μBBB) model. B, Three-dimensional view of the porous membrane at the intersection of the flow channels in the μBBB model. C, Diagram of the microfluidic device containing micro-holes. D, Structure of the synthetic microvasculature model of the BBB model. ACM indicates astrocyte-conditioned medium; BMEC, brain microvascular endothelial cell; and TEER, transendothelial electric resistance.
Figure 4
Figure 4
Suggestions on model selection at early stages of new-drug research and development (R&D). During hit identification stage, simple models, including the monolayer and coculture models, are recommended. microfluidic-based dynamic models may also be used given their incorporation of shear stress and low cost. Because of the large-scale nature of this stage, immortalized endothelial cell lines, especially human cells, should be used. When it comes to the lead identification and optimization stage, the number of compounds is dramatically reduced. Thus, sophisticated sensitive models that better replicate the in vivo blood–brain barrier (BBB) conditions are strongly recommended, such as the coculture models and the dynamic in vitro BBB model. Microfluidic-based dynamic models may also be used at this stage. It is advised to use primary cells at this stage, although cell lines may also be used. BMEC indicates brain micro-vascular endothelial cell.
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