Abstract
Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB) was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs) cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM) from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-α, TNF-α, IL-12p70, IL-1β, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2.
Highlights
Neural stem cells (NSCs) constitute a population that continually self-renews and generates the neurons and glia of the brain
We found that hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), zonulin and Prostaglandin E2 (PGE2) in the absence of epidermal growth factor (EGF) in glioma C6 conditioned media (CM) induced transmigration, that VEGF, zonulin and PGE2 opened the blood brain barrier (BBB), that ReNcells CX expressed CRTAM, occludin and claudins 1, 3 and 4 that might facilitate their paracellular migration and that at the sites of transmigration the expression of occludin and claudin-5 diminished in brain endothelial monolayers
We tested if glioma C6 CM could induce ReNcells CX transmigration across an in vitro BBB model based on the culture of rat brain microvascular endothelial cells (RBMECs)
Summary
Neural stem cells (NSCs) constitute a population that continually self-renews and generates the neurons and glia of the brain. Endogenous neural precursor cells (NPCs) located in the brain subventricular zone have been found to migrate to glial brain tumors [1], where they exert an age dependent antitumorigenic response [2] mediated in part by the release of endovanilloids [3] and bone morphogenetic protein 7 [4] This ability renders the possibility of using NSC for replacing neurons in degenerative disorders, to repress the proliferation of tumor cells and to deliver therapeutic genes to diseased regions in the brain including minute brain metastasis after main tumor resection [for review see [5]. What is more, when NSCs are implanted outside of the CNS intravascularly, they are capable of targeting intracranial gliomas [7]
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