Modeling the blood–brain barrier using stem cell sources

In order to appreciate the potential impact for stem cell modeling of the BBB, it is useful to briefly review the processes of BBB formation and maintenance. Unlike other tissues, central nervous system (CNS) vascularization is exclusively driven by angiogenesis. In rodents, cerebral blood vessels are formed around embryonic day 9 (E9) by sprouting from the perineural vascular plexus (PNVP) [1], a primitive vascular network surrounding the neural tube (Figure 1). Under the influence of vascular endothelial derived growth factor (VEGF), Angiopoietin-1, and sonic hedgehog (Shh) secreted by the neuroepithelium lining the subventricular zone [2], certain endothelial cells (ECs) of the PNVP switch their phenotype to tip cells, a highly invasive and migratory EC type that initiates blood vessel sprouting into the neural tube. Differentiating brain endothelial cells are anchored on a primitive basement membrane (BM) formed by various extracellular matrix (ECM) proteins including collagen IV, fibronectin, laminin-1 and entactin/nidogen-1 [3-5]. Also, the rapid coverage of such newly formed microvasculature by pericytes suggests that they may be the first cell type of the neurovascular unit to physically interact with endothelial cells [5]. In addition to pericytes, neighboring undifferentiated neural progenitor cells (NPCs), differentiating NPCs, and radial glia also appear to exercise an influence on the developmental BBB as studies have suggested their ability to induce barrier properties in brain endothelial cells in vitro and in vivo[6-9]. On the other hand, the early stage developing brain vasculature remains devoid of astrocytes as such cells only appear at the end of gestation and early postnatal stages [10,11]. While the nature of the molecular signals imparted on the brain endothelial cells by the neighboring cells of the developing neurovascular unit remains unclear, recent studies have highlighted the importance of Wnt signaling (through the secretion of Wnt7a/Wn