title: Neural transmembrane protease and endothelial Gs protein activation in cell contact-dependent signaling between neural stem/progenitor cells and brain endothelial cells.
abstract: 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 G(s) 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 G(s) protein signaling at the cell-cell interface. This is the first report of direct cell-cell signaling between NS/P and bEND cells.
authors.affiliation: Institute of Cellular and Systems Medicine, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan, Republic of China.
authors.forename: Hsiu-Hui
authors.initials: HH
authors.lastname: Tung
authors.forename: Sheau-Ling
authors.initials: SL
authors.lastname: Lee
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000166:cytology; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D004805:Ependyma / Q000098:blood supply / Q000166:cytology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055153:Stem Cell Niche / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018925:Chemokines; D017077:Culture Media, Conditioned; D016207:Cytokines; D015850:Interleukin-6; D049452:Green Fluorescent Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D019205:GTP-Binding Protein alpha Subunits, Gs