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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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Good survival of F3.VEGF human neural stem cells pre-labeled with adeno-LacZ (β-gal) was found in hemorrhage core or lesion border of experimental ICH mouse brain 8 weeks post-transplantation. A large number of LacZ+ F3.VEGF human neural stem cells were found to migrate to contralateral side of hemisphere via corpus callosum (A). Higher magnification of migrating F3.VEGF cells is also shown (B–D). LacZ+ F3.VEGF cells differentiate into neurons as shown by β-gal+/NF-L+ (E–G), β-gal+NF-H+ (H–J) and β-gal/MAP2 (K–M) and also into astrocytes as demonstrated by β-gal+/GFAP+ staining (N–P). Bar indicates 50 µm.
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pone-0000156-g006: Good survival of F3.VEGF human neural stem cells pre-labeled with adeno-LacZ (β-gal) was found in hemorrhage core or lesion border of experimental ICH mouse brain 8 weeks post-transplantation. A large number of LacZ+ F3.VEGF human neural stem cells were found to migrate to contralateral side of hemisphere via corpus callosum (A). Higher magnification of migrating F3.VEGF cells is also shown (B–D). LacZ+ F3.VEGF cells differentiate into neurons as shown by β-gal+/NF-L+ (E–G), β-gal+NF-H+ (H–J) and β-gal/MAP2 (K–M) and also into astrocytes as demonstrated by β-gal+/GFAP+ staining (N–P). Bar indicates 50 µm.

Mentions: Following transplantation into ICH mouse cerebral cortex overlying hemorrhage lesion site, β-gal+/LacZ+ human NSCs migrated selectively to the hemorrhagic core and also located on the border of the lesion and further away from the injection sites. We also found β-gal-positive F3.VEGF NSCs to the other brain sites including corpus callosum and hippocampus (Figs. 6A–D). A large number of transplanted β-gal+ F3.VEGF cells (35–45%) differentiated into NF-L+/NF-H+ (Figs. 6E–J) or MAP2+ (Figs. 6K–M) neurons in the peri-hematomal sites. Similarly a large proportion of the transplanted β-gal+ F3.VEGF cells (55–65%) were GFAP+ astrocytes (Figs. 6N–P). Many of the β-gal+/GFAP+ double-positive cells were found along the border of hemorrhagic core. These results indicate that a majority of grafted F3.VGEF cells differentiate into either neurons or astrocytes in response to signals from the local microenvironment provided by the hemorrhagic lesion.


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)

Good survival of F3.VEGF human neural stem cells pre-labeled with adeno-LacZ (β-gal) was found in hemorrhage core or lesion border of experimental ICH mouse brain 8 weeks post-transplantation. A large number of LacZ+ F3.VEGF human neural stem cells were found to migrate to contralateral side of hemisphere via corpus callosum (A). Higher magnification of migrating F3.VEGF cells is also shown (B–D). LacZ+ F3.VEGF cells differentiate into neurons as shown by β-gal+/NF-L+ (E–G), β-gal+NF-H+ (H–J) and β-gal/MAP2 (K–M) and also into astrocytes as demonstrated by β-gal+/GFAP+ staining (N–P). Bar indicates 50 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0000156-g006: Good survival of F3.VEGF human neural stem cells pre-labeled with adeno-LacZ (β-gal) was found in hemorrhage core or lesion border of experimental ICH mouse brain 8 weeks post-transplantation. A large number of LacZ+ F3.VEGF human neural stem cells were found to migrate to contralateral side of hemisphere via corpus callosum (A). Higher magnification of migrating F3.VEGF cells is also shown (B–D). LacZ+ F3.VEGF cells differentiate into neurons as shown by β-gal+/NF-L+ (E–G), β-gal+NF-H+ (H–J) and β-gal/MAP2 (K–M) and also into astrocytes as demonstrated by β-gal+/GFAP+ staining (N–P). Bar indicates 50 µm.
Mentions: Following transplantation into ICH mouse cerebral cortex overlying hemorrhage lesion site, β-gal+/LacZ+ human NSCs migrated selectively to the hemorrhagic core and also located on the border of the lesion and further away from the injection sites. We also found β-gal-positive F3.VEGF NSCs to the other brain sites including corpus callosum and hippocampus (Figs. 6A–D). A large number of transplanted β-gal+ F3.VEGF cells (35–45%) differentiated into NF-L+/NF-H+ (Figs. 6E–J) or MAP2+ (Figs. 6K–M) neurons in the peri-hematomal sites. Similarly a large proportion of the transplanted β-gal+ F3.VEGF cells (55–65%) were GFAP+ astrocytes (Figs. 6N–P). Many of the β-gal+/GFAP+ double-positive cells were found along the border of hemorrhagic core. These results indicate that a majority of grafted F3.VGEF cells differentiate into either neurons or astrocytes in response to signals from the local microenvironment provided by the hemorrhagic lesion.

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