Novel blood brain barrier model
The blood-brain barrier (BBB) is a selectively permeable barrier which separates brain extracellular fluid from circulating blood. It protects the brain from unwanted substances by controlling entry of molecules into the brain.
It is difficult to do large-scale drug screening in vivo to check if new molecules can cross the BBB, and hence there is a need for tissue models. Current tissue models, however, are often unrealistic and difficult to reproduce.
Oxford academics have now developed a fully defined protocol for generating brain microvascular endothelial cells (a particular type of brain cell that forms a crucial part of the BBB), from induced pluripotent stem cells. Uniquely, these cells have similar properties to the equivalent cells in vivo, which for the first time will allow the generation of more realistic BBB models, potentially helping to revolutionise pharmaceutical CNS drug screening.
The blood-brain barrier (BBB) is primarily composed of brain microvascular endothelial cells (BMECs). These BMECs are connected by adherens and tight junctions resulting into high electrical resistance. They are functionally coupled with neurons, astrocytes, mural cells and extracellular matrix components to form so-called neurovascular units.
The BBB is of critical importance when designing and screening for potential therapeutics and many potential candidate drugs acting in the central nervous system will fail to provide their therapeutic effect if they are unable to cross the BBB in sufficient quantity. It is therefore crucial to study the BBB and transport mechanisms across it when developing new therapeutics. However, it is very difficult to do large-scale drug screening to test if new molecules can cross the BBB using in vivo models, and hence there is a need for robust and accurate in vitro models.
Current barriers to success
Existing in vitro models have many drawbacks; they are difficult to reproduce, and often lack sufficient characteristics of a true BBB. The tight junctions between BMECs are often discontinuous in in vitro models and many models also show low trans-endothelial electrical resistance (TEER) measurements. Results from models using non-human mammalian cells often fail to translate to humans. Models that use human immortalised and primary cell lines poorly recapitulate normal physiology, have decreased barrier properties after removal from the brain microenvironment, and limited proliferative ability.
A model example
Oxford academics have developed a new protocol for generating BMECs from induced human pluripotent stem cells, for use in BBB models. It offers many advantages over current methods:
- BMEC properties very similar to those in vivo
- Fully defined protocol
- High reproducibility with different IPSC lines
- Effective barrier formation – high TEER
- Cells can be used by themselves or co-cultured for a more representative in vitro BBB or neurovascular unit model
The technology is subject to a patent application and is now available for license from Oxford University Innovation.
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