Abstract 117: Stromal Cell-derived Factor-1 Gene Modified Endothelial Progenitor Cell Effectively Attenuated Ischemic Brain Injury in Mouse Model

Abstract

Background and purpose: Stromal cell derived factor 1 (SDF-1, also know as CXCL12) is a chemokine that can attract stem cells. We have shown that post-acute SDF1 gene therapy promoted angiogenesis and neurogenesis after ischemic stroke. Transplantation of endothelial progenitor cells (EPC) alone was also beneficial for ischemic stroke recovery. However, it remains unclear whether SDF-1 gene modification of EPC (EPC-SDF-1) can further promote stroke recovery. Here we used lenti-virus (LV) to deliver SDF-1 or GFP gene into EPC, then delivered gene modified EPC cells after permanent middle cerebral artery occlusion (MCAO) to investigate the effect of EPC-SDF-1 on ischemic stroke recovery. Methods and materials: Thirty-eight adult ICR male mice received EPC-SDF-1, EPC-GFP, LV-SDF-1, or PBS stereotactic injection into the peri-infarct area one week after MCAO. Brain atrophy volume, neurobehavioral tests and immunohistochemistry were performed to evaluate the effects of EPC-SDF-1 on angiogenesis and functional repair. Results: Brain atrophy volume was significantly reduced in both gene therapy and cell therapy groups 5 weeks after ischemia (p<0.05; LV-SDF-1 vs. PBS; EPC-GFP vs. PBS; EPC-SDF-1 vs. PBS; n=6), with a smaller atrophy volume in EPC-SDF-1 groups comparing to LV-SDF-1 (p<0.01) and EPC-GFP (p<0.001) group. Neurobehavioral tests including neurological deficits and rotarod test paralleled the result of atrophy volume, with neuronal function improved in all therapeutic groups 5 weeks after ischemic (p<0.001; LV-SDF-1 vs. PBS; EPC-GFP vs. PBS; EPC-SDF-1 vs. PBS; n=8-11), with a better outcome in EPC-SDF-1 group (EPC-SDF-1 vs. LV-SDF-1, p<0.05; EPC-SDF-1 vs. EPC-GFP, p<0.001). The number of CD31 positive blood vessels in peri-infarct area was significantly increased in LV-SDF-1 gene therapy (p<0.05, n=4) and EPC-SDF-1 cell therapy (p<0.001, n=4) group comparing to PBS control. Conclusion: Our results demonstrated that transplantation of SDF-1 gene modified EPC significantly increased angiogenesis after ischemic brain injury; reduced brain atrophy volume and improved the neurological outcomes of the animals. This in vivo data suggests that SDF-1 gene modification of EPC holds great potential in the treatment of ischemic stroke.