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In-vitro blood-brain barrier modeling: A review of modern and fast-advancing technologies.

ABSTRACT: The development of realistic in vitro blood-brain barrier (BBB) models that recapitulate the physiological parameters and molecular aspect of the neurovascular unit (NVU) is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the NVU would provide an invaluable tool to aid in dissecting out the pathological factors, mechanism of action (and corresponding targets) prodromal to the onset of CNS disorders. The field of BBB in vitro modeling has seen many radical changes in the last few years with the introduction on novel technologies and methods to improve over existing models and develop new ones. Therefore, the goal of this review is to provide the readers with updated technical and operational details concerning current BBB platforms with special focus on stem cell technology used to establish a functional BBB model in vitro. Furthermore, we provide a detailed update on rapidly advancing 3D printing technologies used for engineering BBB models which use is now fast expanding among researchers.

SUBMITTER: Sivandzade F

PROVIDER: S-EPMC6168917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The blood-brain barrier (BBB) is formed by brain capillary endothelial cells (BECs) supported by pericytes and astrocytes. The BBB maintains homeostasis and protects the brain against toxic substances circulating in the blood, meaning that only a few drugs can pass the BBB. Thus, for drug screening, understanding cell interactions, and pathology, in vitro BBB models have been developed using BECs from various animal sources. When comparing models of different species, differences exist especially in regards to the transendothelial electrical resistance (TEER). Thus, we compared primary mice, rat, and porcine BECs (mBECs, rBECs, and pBECs) cultured in mono- and co-culture with astrocytes, to identify species-dependent differences that could explain the variations in TEER and aid to the selection of models for future BBB studies. The BBB models based on primary mBECs, rBECs, and pBECs were evaluated and compared in regards to major BBB characteristics. The barrier integrity was evaluated by the expression of tight junction proteins and measurements of TEER and apparent permeability (Papp). Additionally, the cell size, the functionality of the P-glycoprotein (P-gp) efflux transporter, and the expression of the transferrin receptor were evaluated and compared. Expression and organization of tight junction proteins were in all three species influenced by co-culturing, supporting the findings, that TEER increases after co-culturing with astrocytes. All models had functional polarised P-gp efflux transporters and expressed the transferrin receptor. The most interesting discovery was that even though the pBECs had higher TEER than rBECs and mBECs, the Papp did not show the same variation between species, which could be explained by a significantly larger cell size of pBECs. In conclusion, our results imply that the choice of species for a given BBB study should be defined from its purpose, instead of aiming to reach the highest TEER, as the models studied here revealed similar BBB properties.

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In-vitro blood-brain barrier modeling: A review of modern and fast-advancing technologies.

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