The Role And Mechanism Of SDF-1? During Post-acute Phase Of Ischemic Stroke

Ischemic stroke leads to irreversible neurovascular damage both in gray matter and white matter, and the acute interventions of stroke are often challenged by a narrow treatment window. Stromal-derived factor 1(SDF-1, also known as CXCL12) is a chemokine. It modulates neurovascular system development, particularly affects neural cell migration and axon guidance and recruits endothelial progenitor cells(EPCs) for angiogenesis. Endogenous repair of the neurovascular system after ischemic stroke often fails due to the insufficient recruitment of endogenous stem/progenitor cell to the damaged site or the inefficient differentiation into mature cells after ischemia. In this study, I explored SDF-1 gene treatment and SDF-1 gene modified EPC cell(EPC-SDF-1) treatment in the post-acute phase of stroke with wider windows of opportunity. The treatment strategies are designed to promote neurogenesis and angiogenesis, as well as remyelination.We investigated the effects of SDF-1 on neurovascular recovery during the postacute phase and downstream signaling pathways, underlying SDF-1-mediated neurovascular recovery. Adult male ICR mice received stereotactic injection of adeno-associated virus(AAV) mediated SDF-1 gene as treatment or AAV-green fluorescent protein(GFP) as control one week after middle cerebral artery occlusion(MCAO), and were monitored for 5 weeks. The results showed that neurobehavioral outcomes were improved, and brain atrophy was greatly reduced for ?5 weeks in AAV-SDF-1 groups when compared with the control. SDF-1 gene therapy can promote neurogenesis and angiogenesis. Administration of CXCR4 antagonist AMD3100 eliminated the beneficial effects of SDF-1. SDF-1/CXCR4 interaction activated AKT, extracellular signal-regulated kinases(ERK), and P38 mitogen-activated protein kinase(MAPK) signaling pathways but not the c-Jun N-terminal kinase(JNK) pathway. Meanwhile, we found postacute SDF-1 expression promoted the proliferation of oligodendrocyte progenitor cell in the SVZ and their migration to ischemic lesions, as well as protected myelin sheath integrity 5 weeks after ischemia in perifocal area.We used lentivirus(LV) to deliver SDF-1 gene(LV-SDF-1) or GFP(LV-GFP) gene into human umbilical cord blood derived EPC. Adult ICR male mice received EPC-SDF-1, EPC-GFP, LV-SDF-1 and PBS stereotactic injection into the peri-infarct area one week after MCAO. And the results showed that brain atrophy volume was significantly reduced in both gene therapy and cell therapy groups 5 weeks after ischemia in EPC-SDF-1 group. And EPC-SDF-1 cell transplantation significantly protected blood vessels, and promoted angiogenesis and neurogenesis. All the beneficial effect of EPC-SDF-1 cell transplantation may be related with the increased expression of VEGF protein and higher capacity of tubeformation and cell viability.Over all, this dissertation focuses on the roles of SDF-1 gene and EPC-SDF-1 cell therapy during post-acute phase of ischemia, and the underlying mechanisms, which suggests that they may be promising therapeutic strategies for ischemic stroke patients with a wider treatment window.