Neural Transmembrane Protease and Endothelial Gs Protein Activation in Cell Contact-dependent Signaling between Neural Stem/Progenitor Cells and Brain Endothelial Cells

Vasculature is an important component of the neural stem cell niche in brain. It regulates neural stem/progenitor (NS/P) cell self-renewal, differentiation, and migration. In the neurogenic niches of adult brain, NS/P cells lie close to blood vessels, and proliferating NS/P cells frequently contact the vasculature. In the present study we showed that NS/P cells in co-culture with brain endothelial (bEND) cells activated endothelial G proteins and p38 mitogen-activated protein kinase (p38 MAPK) and stimulated cytokine/chemokine expression. These NS/P cell-induced endothelial responses took place during NS/P cell and bEND cell direct contact and were critically dependent on the expression of the type II transmembrane serine protease matriptase (MTP) by NS/P cells, because knocking down of MTP in NS/P cells impaired and re-expression of MTP restored their ability to induce endothelial cytokine/chemokine expression, p38 MAPK, or G protein activation. Cholera toxin blocked NS/P cell-induced endothelial responses, suggesting that the endothelial G protein activated by NS/P MTP is in the Gs subfamily. The addition of p38 MAPK inhibitor impaired NS/P cell-induced endothelial cytokine/chemokine expression. The known G protein-coupled receptor substrate of MTP, protease-activated receptor 2, was not involved in this system. These results revealed a novel signaling pathway in neural stem cell vascular niches that is mediated by neural MTP and endothelial Gs protein signaling at the cell-cell interface. This is the first report of direct cell-cell signaling between NS/P and bEND cells. Background: Vasculature is a key component of the brain neurogenic stem cell niche. Results: Knockdown of matriptase/epithin in neural progenitor cells or blocking of Gs protein activity in brain endothelial cells impairs contact-induced endothelial signaling activation and gene stimulation. Conclusion: Matriptase/epithin and Gs protein signaling guide contact communication in neurovascular niche. Significance: The study advances our understanding of cell-cell communication in the neurogenic vascular niche.