A novel hypothesis of blood-brain barrier (BBB) development and in vitro BBB model: neural stem cell is the driver of BBB formation and maintenance

There is an ongoing effort to develop in vitro models for the blood-brain barrier (BBB) research and the central nervous system (CNS) drug screening. But the phenotypes of the existing in vitro models are still very remote from those found in vivo. The trouble in establishing in vitro BBB models comes from the unclear mechanism of the BBB formation and maintenance. The astrocytes have been found to be responsible for the maintenance of the BBB, but the studies of the CNS development have shown that the BBB formation starts largely before the gliogenesis. We hypothesize here that the neural stem cell is the real driver of the BBB formation, development and maintenance. The formation of the BBB is initiated by the neural stem cells during the earliest stage of CNS angiogenesis. The maintenance of the BBB is driven by the soluble signals produced by the neural stem cells which exist in the dentate gyrus of the hippocampus and the subventricular zone throughout the life. The brain microvascular endothelial cells (BMEC)-pericyte complex is the anatomical basis of the BBB. Based on our hypothesis we suggest using the neural stem cells to induce the BMECpericyte complex to establish in vitro BBB models. The further research on the role of the neural stem cells in the BBB formation and maintenance may elucidate the mechanism of the BBB development.