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Rosa, Alexandra I.; Grade, Sofia; Santos, Sofia D.; Bernardino, Liliana; Chen, Thomas C.; Relvas, Joao; Hofman, Florence M.; Agasse, Fabienne (2016): Heterocellular Contacts with Mouse Brain Endothelial Cells Via Laminin and alpha 6 beta 1 Integrin Sustain Subventricular Zone (SVZ) Stem/Progenitor Cells Properties. In: Frontiers in Cellular Neuroscience, Vol. 10, 284
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Abstract

Neurogenesis in the subventricular zone (SVZ) is regulated by diffusible factors and cell-cell contacts. In vivo, SVZ stem cells are associated with the abluminal surface of blood vessels and such interactions are thought to regulate their neurogenic capacity. SVZ neural stem cells (NSCs) have been described to contact endothelial-derived laminin via (01 integrin. To elucidate whether heterocellular contacts with brain endothelial cells (BEG) regulate SVZ cells neurogenic capacities, cocultures of SVZ neurospheres and primary BEG, both obtained from C57BL/6 mice, were performed. The involvement of laminin integrin interactions in SVZ homeostasis was tested in three ways. Firstly, SVZ cells were analyzed following incubation of BEC with the protein synthesis inhibitor cycloheximide (GHX) prior to coculture, a treatment expected to decrease membrane proteins. Secondly, SVZ cells were cocultured with BEG in the presence of an anti-alpha 6 integrin neutralizing antibody. Thirdly, BEC were cultured with beta 1(-/-) SVZ cells. We showed that contact with BEC supports, at least in part, proliferation and stemness of SVZ cells, as evaluated by the number of BrdU positive (+) and Sox2+ cells in contact with BEG. These effects are dependent on BEG-derived laminin binding to alpha 6 beta 1 integrin and are decreased in cocultures incubated with anti-alpha 6 integrin neutralizing antibody and in cocultures with SVZ beta 1(-/-) cells. Moreover, BEG-derived laminin sustains sternness in SVZ cell cultures via activation of the Notch and mTOR signaling pathways. Our results show that BEC/SVZ interactions involving alpha 6 beta 1 integrin binding to laminin, contribute to SVZ cell proliferation and stemness.