In vitro models of the blood–brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use

Abstract

The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This "blood-brain barrier" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established blood-brain barrier characteristics. As an ideal cell culture model of the blood-brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.

Primary Porcine Brain Endothelial Cells as In Vitro Model to Study Effects of Ultrasound and Microbubbles on Blood–Brain Barrier Function

“…However, to allow valid conclusions in an in vitro BBB model, several important requirements must be fulfilled. These include low permeability, presence of developed tight junctions, expression of efflux pumps, presence of polarized receptor systems and responsiveness to cells present at the neurovascular unit [17].…”

Literature review and appraisal on alternative neurotoxicity testing methods

“…In its basic state TEER values from these cells are not comparable with the in vivo situation or animal based models. This model therefore offers barrier function for only large molecules, whereas small molecules relatively easily permeate the barrier (Helms et al, 2016b). Although there are several articles that show limited barrier function of this cell model (Eigenmann et al, 2013;Hatherell et al, 2011) different culture condition for example dynamic culture system and/or co-culture with pericytes and/or astrocytes might improve the barrier function and make this a useful model for permeability screening.…”

“…give an overview of established in vitro BBB models up until 2016 (Banerjee et al, 2016a;Helms et al, 2016a;Wolff et al, 2015b). Starting from these reviews the full text screening was only performed for studies that were published in 2016 and 2017.…”

“…Efflux transport systems like the ABC-type transporters transport hydrophobic molecules out of the cell back into the lumen and thereby prevent them from reaching the CNS. The high metabolizing capacity of astrocytes metabolizes hydrophobic compounds that permeated into the neurovascular unit (Banerjee et al, 2016b;Helms et al, 2016b).…”

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

“…A much more comprehensive battery of techniques is already in regular use in the pharmaceutical industry, including genomics, transcriptomics, and proteomics. In recent MPS studies, we are seeing functional measurements such as contractility, calcium signaling, and electrophysiological responses of cardiac and skeletal muscle, 37,[69][70][71][72][73][74][75] electrical resistance and molecular permeability of barriers, [76][77][78][79][80][81][82] and metabolomic responses to inflammatory challenges. 78 In this issue, the Parker group uses a variety of measures, including gene expression profiling, to quantify factors that affect maturation of neonatal rat cardiomyocytes into a more mature phenotype.…”