Monodimensional Models of the Blood Brain Barrier Endothelial Cells

The most commonly used model to study the blood-brain barrier in vitro stems from a rather simplified view of the BBB and consists of the so-called "Transwell system," where cells are grown on porous membranes and immersed in growth media (Figure 1). A variety of cells have been successfully grown under these conditions, including, but not limited to, endothelial and epithelial cells from rodents, primates, or human origin. The most attractive features of this model are its simplicity and the ability to perform several experiments at the same time. Many Transwells can be simultaneously loaded with cells or cell lines, and experiments can therefore be rapidly performed, minimizing the cost and need for an experimenter's skills. However, the major pitfalls of this system are that cells are grown in the absence of physiological stimuli, such as perivascular glia, shear stress, or interaction with blood cells present in the cerebral circulation under normal conditions, develop an abnormal permeability across the EC layer. Another limitation of this system is that cells are grown in the presence of serum, on both the luminal and abluminal sides. Conversely, in vivo, only the luminal side is exposed to serum proteins and the abluminal part is exposed to glial influences or cere-

Figure 1 Schematic representation of the Transwell system. Either monodimensional endothelial cultures (left) or bidimensional endothelial-astrocyte coculture can be established (right). (see color insert)

Table I Advantages and Disadvantages of Each Model Used to Study the BBB in Vitro.

Monodimensional (Transwell)

Bidimensional (coculture)

Tridimensional (DIV-BBB)

Pros

Cons

Ease of use

Ideal for Michaelis-Menten kinetics of transport due to fixed volumes in each compartment Can do several experiments at same time Minimal skills Cost efficient

Lacks physiological flow High permeability to sucrose Low TEER

Exposure to serum on both sides (luminal + abluminal)

Coculture allows induction of BBB

properties Molecule flux across is lower than monodimensional Cost efficient

Lacks physiological flow High permeability to sucrose Low TEER (to a lesser extent)

Artificial capillaries connected by gas-permeable tubing allows source of growth medium, exchange of O2+CO2, exposure to flow Induction of BBB properties High TEER

Low permeability to sucrose Stereoselective transport

Can mimic intravenous/intra-abdominal delivery versus administration by mouth Long term studies possible Presence of drug extrusion mechanisms Linear kinetic studies more difficult, because of flow Cost Skills

Number of cells to be loaded/used brospinal fluid. In conclusion, monodimensional cultures based on endothelial cells lack true physiological "barrier function." However, Galla and his colleagues have shown that with the addition of hydrocortisone to serum, the barrier function greatly improves [3]. The physiopathological significance of these findings is unclear, but the modification provided by these investigators greatly improved the usefulness of these models.

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