Abstract
BackgroundIschemic stroke causes a multitude of brain damage. Neurovascular injury and myelin sheath degradation are two manifestations of ischemic brain damage. Therapeutic strategies aiming only at repairing the neural components or the vessels cannot efficiently restore neurological function. Endothelial progenitor cells (EPCs) have the advantages of both promoting angiogenesis and secreting trophic factors that would promote neurogenesis. Chemokine cxcl12 gene therapy has also been shown to promote angiogenesis, neurogenesis, and remyelination, attracting EPCs, neural progenitor cells, and oligodendrocyte progenitor cells (OPCs) to the injured sites of the brain. In this work, we tested whether these two therapeutics can be combined by genetically engineering the EPCs with cxcl12 to harness the synergistic effects of these two interventions.MethodsWe used lentivirus (LV) to deliver cxcl12 gene into human umbilical cord blood EPCs to generate the engineered CXCL12-EPCs, which were then delivered into the perifocal region at 1 week after permanent middle cerebral artery occlusion to investigate the effects of CXCL12-EPCs on the functional recovery and angiogenesis, neurogenesis, and remyelination in ischemic stroke mice. Green fluorescent protein (gfp) gene-modified EPCs and LV-CXCL12 gene therapy were used as controls.ResultsCXCL12-EPC treatment significantly reduced brain atrophy and improved neurobehavioral function at 5 weeks after brain ischemia. The treatment resulted in increased blood vessel density and myelin sheath integrity, and promoted neurogenesis, angiogenesis, and the proliferation and migration of OPCs. In-vitro data showed that CXCL12-EPCs performed better in proliferation and tube formation assays and expressed a higher level of vascular endothelial growth factor compared to GFP-EPCs.ConclusionsThe synergistic treatment of CXCL12-EPCs outperformed the single therapies of GFP-EPCs or LV-CXCL12 gene therapy in various aspects related to post-ischemic brain repair. cxcl12-engineered EPCs hold great potential in the treatment of ischemic stroke.
Highlights
Ischemic stroke causes a multitude of brain damage
Green fluorescent protein (GFP) green fluorescent protein, Endothelial progenitor cell (EPC) endothelial progenitor cells, GFP-EPC endothelial progenitor cell modified by gfp gene, CXCL12-EPC endothelial progenitor cell modified by cxcl12 gene
Phosphate-buffered saline (PBS) phosphate-buffered saline, GFP-EPC endothelial progenitor cell modified by gfp gene, GFP green fluorescent protein, CXCL12-EPC endothelial progenitor cell modified by cxcl12 gene twice with 0.1 mol/L sodium borate for 10 min each
Summary
Neurovascular injury and myelin sheath degradation are two manifestations of ischemic brain damage. Therapeutic strategies aiming only at repairing the neural components or the vessels cannot efficiently restore neurological function. Chemokine cxcl gene therapy has been shown to promote angiogenesis, neurogenesis, and remyelination, attracting EPCs, neural progenitor cells, and oligodendrocyte progenitor cells (OPCs) to the injured sites of the brain. Cerebral ischemia causes a cascade of detrimental events, including excitotoxicity, peri-infarct polarization, blood– brain barrier impairment, inflammation, and apoptosis, resulting in a multitude of injuries among which neurovascular damage and myelin sheath degradation are two signature events [1,2,3,4], which together result in failed or false signal transduction at the cellular level, causing the various deficits of neural behavioral function in patients. Compared to the relatively narrow treatment window of thrombolytic tissue plasminogen activator (tPA) [7] and endovascular thrombectomy, the longer subacute phase presents additional opportunities for intervention
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