Abstract
In a previous study, we have shown that human neural stem cells (hNSCs) transplanted in brain of mouse intracerebral hemorrhage (ICH) stroke model selectively migrate to the ICH lesion and induce behavioral recovery. However, low survival rate of grafted hNSCs in the brain precludes long-term therapeutic effect. We hypothesized that hNSCs overexpressing Akt1 transplanted into the lesion site could provide long-term improved survival of hNSCs, and behavioral recovery in mouse ICH model. F3 hNSC was genetically modified with a mouse Akt1 gene using a retroviral vector. F3 hNSCs expressing Akt1 were found to be highly resistant to H2O2-induced cytotoxicity in vitro. Following transplantation in ICH mouse brain, F3.Akt1 hNSCs induced behavioral improvement and significantly increased cell survival (50–100% increase) at 2 and 8 weeks post-transplantation as compared to parental F3 hNSCs. Brain transplantation of hNSCs overexpressing Akt1 in ICH animals provided functional recovery, and survival and differentiation of grafted hNSCs. These results indicate that the F3.Akt1 human NSCs should be a great value as a cellular source for the cellular therapy in animal models of human neurological disorders including ICH.
Highlights
IntroductionTwo major types of stroke are cerebral infarction (ischemia) and intracerebral hemorrhage (ICH)
Two major types of stroke are cerebral infarction and intracerebral hemorrhage (ICH)
Transcripts for nestin, neurofilament triplet proteins (NF-L, NF-M and NF-H, cell type-specific markers for neurons), glial fibrillary acidic protein (GFAP, a specific marker for astrocytes) and Akt1 are all expressed by both F3 and F3.Akt1 cells
Summary
Two major types of stroke are cerebral infarction (ischemia) and intracerebral hemorrhage (ICH). 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. We have previously reported that human NSC line ameliorate neurological deficits in animal models of Parkinson disease [18], Huntington disease [19,20], amyotrophic lateral sclerosis [21] and lysosomal storage disease [22] following their transplantation into the brain or spinal cord. Low survival rate of grafted F3 NSCs in ischemia and ICH rats in the previous studies is a grave concern; less than 50% of grafted NSCs survived in ICH mice at 2-weeks post transplantation and 30% at 8-weeks [15,16]
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