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

Hong J Lee,Seung U Kim,Kwang S Kim,In H Park,Maarten Van Lohuizen

doi:10.1371/journal.pone.0000156

Hong J Lee, Seung U Kim + Show 3 more

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https://doi.org/10.1371/journal.pone.0000156

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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.

Highlights

Intracerebral hemorrhage (ICH) represents at least 15% of all strokes in the western population and a considerably higher proportion at 50–60% in the oriental populations in Korea, Chin and Japan [1,2]
In PBS-injected ICH animals, vascular endothelial growth factor (VEGF) contents were below the detectable level of the VEGF ELISA assay. These results indicate that F3.VEGF neural stem cells (NSCs) at the ICH lesion sites are capable of producing markedly higher amount of VEGF than the parental F3 cells in the lesion sites and capable of providing neuroprotective and neoangiogenetic action in the ICH injury sites resulting in improved behavioral outcome
An animal model of intracerebral hemorrhage (ICH) was used to provide proof-of-principle that human NSCs over-expressing growth factor VEGF can be transplanted in the brain of animal models of neurological diseases, and produce beneficial effects of functional recovery, increased angiogenesis in the host brain and increased survival of grafted NSCs

Summary

Introduction

Intracerebral hemorrhage (ICH) represents at least 15% of all strokes in the western population and a considerably higher proportion at 50–60% in the oriental populations in Korea, Chin and Japan [1,2]. Primary human NSCs derived from fetal tissues can be provided for only a limited time before they undergo senescence, and it is difficult to secure sufficient numbers and homogeneous populations of human NSCs from fetal brain These problems can be circumvented by the use of stable, permanent cell lines of human NSCs. Intracerebral hemorrhage (ICH) is a lethal stroke type. 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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