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Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model.

Lee HJ, Kim KS, Park IH, Kim SU - PLoS ONE (2007)

Bottom Line: 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.Brain 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.

View Article: PubMed Central - PubMed

Affiliation: Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea.

ABSTRACT

Background: Intracerebral 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 findings: We 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.

Conclusions: Brain 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.

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Related in: MedlinePlus

At 8 weeks post-transplantation in the hemorrhage core border areas, the number of TUNEL (in situ end-labeling of nuclear DNA fragmentation)-positive cells was highest in PBS-ICH control animals (A), while the number of TUNEL-positive cells is much lower in the ICH-F3 (B) or ICH-F3.VEGF groups (C). Bar indicates 100 µm.
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pone-0000156-g008: At 8 weeks post-transplantation in the hemorrhage core border areas, the number of TUNEL (in situ end-labeling of nuclear DNA fragmentation)-positive cells was highest in PBS-ICH control animals (A), while the number of TUNEL-positive cells is much lower in the ICH-F3 (B) or ICH-F3.VEGF groups (C). Bar indicates 100 µm.

Mentions: A large number of TUNEL (in situ end-labeling of nuclear DNA fragmentation)-positive cells were found in the brain sections in the PBS-ICH control animals. At 8 weeks post- transplantation in the hemorrhage core border areas, the number of TUNEL-positive cells was much lower in the ICH animals receiving transplantation of F3.VEGF cells than ICH animals receiving PBS or F3 cells (Fig. 8A–D). The number of TUNEL-positive cells in ICH/F3.VEGF brain was similar in the lateral or medial borders. This pattern was similar in ICH mice grafted with F3 cells. Interestingly, the number of TUNEL-positive cells bearing nuclear DNA fragments was significantly reduced in the medial border of the hemorrhage core, which was in the vicinity of the F3.VEGF grafts, but not in the lateral border, away from the NSC grafts.


Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model.

Lee HJ, Kim KS, Park IH, Kim SU - PLoS ONE (2007)

At 8 weeks post-transplantation in the hemorrhage core border areas, the number of TUNEL (in situ end-labeling of nuclear DNA fragmentation)-positive cells was highest in PBS-ICH control animals (A), while the number of TUNEL-positive cells is much lower in the ICH-F3 (B) or ICH-F3.VEGF groups (C). Bar indicates 100 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1764718&req=5

pone-0000156-g008: At 8 weeks post-transplantation in the hemorrhage core border areas, the number of TUNEL (in situ end-labeling of nuclear DNA fragmentation)-positive cells was highest in PBS-ICH control animals (A), while the number of TUNEL-positive cells is much lower in the ICH-F3 (B) or ICH-F3.VEGF groups (C). Bar indicates 100 µm.
Mentions: A large number of TUNEL (in situ end-labeling of nuclear DNA fragmentation)-positive cells were found in the brain sections in the PBS-ICH control animals. At 8 weeks post- transplantation in the hemorrhage core border areas, the number of TUNEL-positive cells was much lower in the ICH animals receiving transplantation of F3.VEGF cells than ICH animals receiving PBS or F3 cells (Fig. 8A–D). The number of TUNEL-positive cells in ICH/F3.VEGF brain was similar in the lateral or medial borders. This pattern was similar in ICH mice grafted with F3 cells. Interestingly, the number of TUNEL-positive cells bearing nuclear DNA fragments was significantly reduced in the medial border of the hemorrhage core, which was in the vicinity of the F3.VEGF grafts, but not in the lateral border, away from the NSC grafts.

Bottom Line: 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.Brain 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.

View Article: PubMed Central - PubMed

Affiliation: Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea.

ABSTRACT

Background: Intracerebral 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 findings: We 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.

Conclusions: Brain 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.

Show MeSH
Related in: MedlinePlus