Transmigration of neural stem cells across the blood brain barrier induced by glioma cells

PLoS One. 2013 Apr 5;8(4):e60655. doi: 10.1371/journal.pone.0060655. Print 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Blood-Brain Barrier / cytology*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Cell Line, Tumor
  • Cholera Toxin / pharmacology
  • Claudins / metabolism
  • Culture Media, Conditioned / metabolism
  • Dinoprostone / pharmacology
  • Electrophysiological Phenomena / drug effects
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects
  • Glioma / pathology*
  • Haptoglobins
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Immunoglobulins / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Occludin / metabolism
  • Protein Precursors
  • Rats
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Transendothelial and Transepithelial Migration* / drug effects
  • Vascular Endothelial Growth Factor A / pharmacology


  • Claudins
  • Culture Media, Conditioned
  • Haptoglobins
  • Immunoglobulins
  • Occludin
  • Protein Precursors
  • Vascular Endothelial Growth Factor A
  • class-I restricted T cell-associated molecule
  • zonulin
  • Hepatocyte Growth Factor
  • Cholera Toxin
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Dinoprostone

Grant support

This work was supported by the Mexican Council of Science and Technology, CONACYT (Consejo Nacional de Ciencia y Technologia) (URL:, grants98448 (LGM) and 127357 (JS) and by a multidisciplinary grant from CINVESTAV (Centro de Investigacióny de Estudios Avanzados del Instituto Politécnico Nacional) (URL: Mónica Díaz Coránguez, Adolfo López -Ornelas and Henry Puerta were recipients of doctoral fellowships from CONACYT (267383, 206882 and 225017). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.