Modeling the blood-brain barrier: Beyond the endothelial cells

The blood-brain barrier (BBB) regulates the transport of ions, nutrients, and metabolites to help maintain proper brain function. This restrictive interface formed by brain microvascular endothelial cells excludes the majority of small and large molecule drugs from entering the brain, and blood-brain barrier dysfunction is a signature of many neurological diseases. Thus, in vitro models of the BBB based on brain endothelial cells have been developed to facilitate screening drugs for BBB permeability. However, while brain endothelial cells form the main interface, they work in concert with other brain-resident cells such as neural progenitor cells, pericytes, astrocytes, and neurons to form the neurovascular unit (NVU). Importantly, non-endothelial cells of the NVU play key roles in eliciting BBB phenotypes and in regulating the dynamic responses of the BBB to brain activity and disease. As a result, emerging in vitro BBB models have incorporated these NVU cell types in addition to endothelial cells. These multicellular BBB or NVU models have found increasing application not only in drug screening, but also in studying complex cellular and molecular mechanisms underlying BBB biology and disease.