Stromal cell-derived factor 1 alpha mediates neural progenitor cell motility after focal cerebral ischemia

In the adult rodent, stroke induces an increase in endogenous neural progenitor cell (NPC) proliferation in the subventricular zone (SVZ) and neuroblasts migrate towards the ischemic boundary. We investigated the role of stromal cell-derived factor 1 alpha (SDF-1 alpha) in mediating NPC migration after stroke. We found that cultured NPCs harvested from the normal adult SVZ, when they were overlaid onto stroke brain slices, exhibited significantly (P < 0.01) increased migration (67.2 +/- 25.2 mu m) compared with the migration on normal brain slices (29.5 +/- 29.5 mu m). Immunohistochemistry showed that CXCR 4, a receptor of SDF-1 alpha, is expressed in the NPCs and migrating neuroblasts in stroke brain. Blocking SDF-1 alpha by a neutralizing antibody against CXCR 4 significantly attenuated stroke-enhanced NPC migration. ELISA analysis revealed that SDF-1 alpha levels significantly increased (P < 0.01) in the stroke hemisphere (43.6 +/- 6.5 pg/mg) when compared with the normal brain (25.2 +/- 1.9 pg/mg). Blind-well chamber assays showed that SDF-1 alpha enhanced NPC migration in a dose-dependent manner with maximum migration at a dose of 500 ng/mL. In addition, SDF-1 alpha induced directionally selective migration. These findings show that SDF-1 alpha generated in the stroke hemisphere may guide NPC migration towards the ischemic boundary via binding to its receptor CXCR 4 in the NPC. Thus, our data indicate that SDF-1 alpha/CXCR 4 is important for mediating specific migration of NPCs to the site of ischemic damaged neurons.