Title:Radial Glia-endothelial Cells’ Bidirectional Interactions Control Vascular Maturation and Astrocyte Differentiation: Impact for Blood-brain Barrier Formation
Volume: 16
Issue: 4
Author(s): Siqueira M. da Silva, Gisbert D. Campos, Flávia C.A. Gomes and Joice Stipursky*
Affiliation:
- Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro - RJ, 21941-901,Brazil
Keywords:
Radial glia-endothelial cells, cerebral cortex, neural stem cell, astrocytes, blood-brain barrier, isolated microcapillary
brain endothelial cells, vascular development, gliogenesis.
Abstract:
Background: In the developing cerebral cortex, Radial Glia (RG) multipotent neural
stem cell, among other functions, differentiate into astrocytes and serve as a scaffold for blood
vessel development. After some time, blood vessel Endothelial Cells (ECs) become associated
with astrocytes to form the neurovascular Blood-Brain Barrier (BBB) unit.
Objective: 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.
Methods: 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).
Results: Finally, we demonstrated that isolated RG cells cultures treated with MBEC conditioned
medium promoted the differentiation of astrocytes in a Vascular Endothelial Growth Factor-A
(VEGF-A) dependent manner.
Conclusion: 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.
