Radial glia-Endothelial cells bidirectional interactions control vascular maturation and astrocyte differentiation: impact for blood brain barrier formation.Curr Neurovasc Res 2019CN
In the developing cerebral cortex, radial glia (RG) multipotent neural stem, among other functions, differentiate into astrocytes and serve as a scaffold for blood vessel development. Later on, blood vessel endothelial cells (ECs) associate with astrocytes to form the neurovascular blood brain barrier (BBB) unit.
Since little is known about the mechanisms underlying bidirectional RG-ECs interactions in both vascular development and astrocyte differentiation, this study investigated the impact of interactions between RG and ECs mediated by secreted factors on EC maturation and gliogenesis control.
First, we demonstrated that immature vasculature in the murine embryonic cerebral cortex physically interacts with Nestin positive RG neural stem cells in vivo. Isolated microcapillary brain endothelial cells (MBEC) treated with the conditioned medium from RG cultures (RG-CM) displayed decreased proliferation, reduction in the protein levels of the endothelial tip cell marker Delta-like 4 (Dll4), and decreased expression levels of the vascular permeability associated gene, plasmalemma vesicle associated protein-1 (PLVAP1). These events were also accompanied by increased levels of the tight junction protein expression, zonula occludens-1 (ZO-1).
Finally, we demonstrated that isolated RG cells cultures treated with MBEC conditioned medium promoted astrocyte differentiation into astrocytes in a vascular endothelial growth factor - A (VEGF-A) dependent manner.
These results suggest that the bidirectional interaction between RG and ECs is essential to induce vascular maturation and astrocyte generation, which may be an essential cell-cell communication mechanism to promote BBB establishment.