Human Neural Stem Cells Over-Expressing VEGF Provide Neuroprotection, Angiogenesis and Functional Recovery in Mouse Stroke Model

Abstract

BackgroundIntracerebral hemorrhage (ICH) is a lethal stroke type. As mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and induce behavioral recovery in rat ICH model, and that combined administration of NSCs and vascular endothelial growth factor (VEGF) results in improved structural and functional outcome from cerebral ischemia.Methods and FindingsWe postulated that human NSCs overexpressing VEGF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs, increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by unilateral injection of bacterial collagenase into striatum. HB1.F3.VEGF human NSC line produced an amount of VEGF four times higher than parental F3 cell line in vitro, and induced behavioral improvement and 2–3 fold increase in cell survival at two weeks and eight weeks post-transplantation.ConclusionsBrain transplantation of F3 human NSCs over-expressing VEGF near ICH lesion sites provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results suggest a possible application of the human neural stem cell line, which is genetically modified to over-express VEGF, as a therapeutic agent for ICH-stroke.

Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice

“…[31][32][33][34]37,38 The genetically modified human NSCs we established, F3.VEGF cells, were confirmed to release four times of VEGF165, the most abundant and biologically active isoform in vivo, compared with the parental F3 cells as we have reported previously in animal models of stroke. 28 Ex vivo gene therapy by genetically modified cells to carry growth factor gene has no risk related with virus injection during the in vivo gene therapy, and the transplanted cells can deliver growth factor over a large area as the cells migrate and are integrated to the host brain tissue. Moreover, transplantation of NSCs may afford healthy glial cells that are derived from the NSCs to a diseased environment.…”

“…VEGF is an angiogenetic growth factor acting as a potent mitogen and survival factor for endothelial cells, 20,21 smooth muscle cells, 22,23 hepatocytes 24 and cardiomyocytes, 25,26 and also known for neuroprotective effect against brain injury. 27,28 Several recent studies have also shown that VEGF promoted cell survival pathways and blocked cell death in the ALS animal model. [16][17][18][19]29,30 VEGF is the neurotrophic growth factor that can be used in combination with transplanted stem cells to improve therapeutic efficiency of cellular transplantation.…”

High Serum Levels of Growth Factors Are Associated with Good Outcome in Intracerebral Hemorrhage

“…Similarly, it has been shown that human neural stem cells overexpressing VEGF provide neuroprotection, angiogenesis, and functional recovery in a mouse ICH model (Lee et al, 2007). Other growth factors (GFs) have also been involved in neurorepair after ICH.…”

Human-Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke-Damaged Brain

“…Human fetal NSCs also gave rise to mature neurons after transplantation into the stroke-damaged rat brain [7][8][9]. Transplanted NSCs may promote recovery without differentiating to neurons through several other mechanisms, for example, modulation of inflammation [10][11][12], neuroprotection [12], stimulation of angiogenesis [11,13,14], and enhancing brain plasticity [15][16][17].…”