Stromal Cell-Derived Factor 1α Mediates Neural Progenitor Cell Motility after Focal Cerebral Ischemia

Abstract

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 1a (SDF-1a) 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 (Po0.01) increased migration (67.27 25.2 lm) compared with the migration on normal brain slices (29.5729.5 lm). Immunohistochemistry showed that CXCR 4, a receptor of SDF-1a, is expressed in the NPCs and migrating neuroblasts in stroke brain. Blocking SDF-1a by a neutralizing antibody against CXCR 4 significantly attenuated stroke-enhanced NPC migration. ELISA analysis revealed that SDF-1a levels significantly increased (Po0.01) in the stroke hemisphere (43.676.5 pg/mg) when compared with the normal brain (25.27 1.9 pg/mg). Blind-well chamber assays showed that SDF-1a enhanced NPC migration in a dosedependent manner with maximum migration at a dose of 500 ng/mL. In addition, SDF-1a induced directionally selective migration. These findings show that SDF-1a 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-1a/CXCR 4 is important for mediating specific migration of NPCs to the site of ischemic damaged neurons.

Meteorin is a Chemokinetic Factor in Neuroblast Migration and Promotes Stroke-Induced Striatal Neurogenesis

“…Stromal cell-derived factor 1a levels are increased in the injured hemisphere (Robin et al, 2006) and CXCR4 is expressed on neural progenitors and stroke-generated neuroblasts (Robin et al, 2006). Neuroblast migration is markedly attenuated by blocking CXCR4 (Robin et al, 2006;Thored et al, 2006). Other factors promoting neuroblast migration after stroke are monocyte chemoattractant protein-1 (Yan et al, 2007), matrix metalloproteinase-9 (Lee et al, 2006), and osteopontin (Yan et al, 2009).…”

How stem cells speak with host immune cells in inflammatory brain diseases

“…The activation of the CXCR4/SDF-1α signaling pathway on NPCs and MSCs increases their migratory capacity, survival, and remyelinating capacity, both in vitro on slice cultures (Corti et al, 2005;Imitola et al, 2004b), as well as in vivo upon focal transplantation into rodents with experimental cerebral ischemia (Robin et al, 2006;Wang et al, 2008), and JHMV-induced demyelination (Carbajal et al, 2010(Carbajal et al, , 2011. In human NPCs, integrins α2, α6, and β preferentially mediate the homing toward the vasculature, whereas the CXCR4/ SDF-1α signaling pathway regulates homing through the brain parenchyma (Carbajal et al, 2010;Mueller et al, 2006;van der Meulen et al, 2009).…”

Cell Therapy for Multiple Sclerosis

“…Tumor necrosis factor-α increases the motility of neural precursors in vitro [99]. The chemokine stromal derived factor 1 (CXCL12) induces neural stem/precursor cell migration in models of stroke [100,101], viral-induced demyelination [102], and trauma [103]. In addition, the injection of inflammatory stimuli in an ex vivo model of hippocampal slices attracted neural precursors, depending of monocyte chemoattractant protein (MCP-1) signaling via the CCR2 receptor [104].…”

“…Several chemokines were shown to be expressed in the inflamed brain [272]. Among these, stromal derived factor 1 was shown to induce neural stem/ precursor cells migration in stroke [100,101], viralinduced demyelination [102], and trauma [103]. MCP-1 and its receptor CCR2 were shown to modulate neural precursor cell migration following cerebral ischemia [169].…”