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Transplantation of neural stem cells that overexpress SOD1 enhances amelioration of intracerebral hemorrhage in mice.

ABSTRACT: Previous studies have shown that intraparenchymal transplantation of neural stem cells (NSCs) ameliorates neurologic deficits in animals with intracerebral hemorrhage (ICH). However, massive grafted cell death after transplantation, possibly caused by a hostile host brain environment, lessens the effectiveness of this approach. We focused on the effect of oxidative stress against grafted NSCs and hypothesized that conferring antioxidant properties to transplanted NSCs may overcome their death and enhance neuroprotection after ICH. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. We investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted NSCs and accelerates amelioration of ICH. Neural stem cells that overexpress SOD1 were administered intracerebrally 3 days after ICH in a mouse model. Histologic and behavioral tests were examined after ICH. Copper/zinc-superoxide dismutase overexpression protected the grafted NSCs via a decrease in production of reactive oxygen species. This resulted in an increase in paracrine factors released by the NSCs, and an increase in surviving neurons in the striatum and a reduction in striatal atrophy. In addition, SOD1 overexpression showed progressive improvement in behavioral recovery. Our results suggest that enhanced antioxidative activity in NSCs improves efficacy of stem cell therapy for ICH.

SUBMITTER: Wakai T

PROVIDER: S-EPMC3948120 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Transplantation of neural stem cells that overexpress SOD1 enhances amelioration of intracerebral hemorrhage in mice.

Wakai Takuma T Sakata Hiroyuki H Narasimhan Purnima P Yoshioka Hideyuki H Kinouchi Hiroyuki H Chan Pak H PH

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20131211 3

Previous studies have shown that intraparenchymal transplantation of neural stem cells (NSCs) ameliorates neurologic deficits in animals with intracerebral hemorrhage (ICH). However, massive grafted cell death after transplantation, possibly caused by a hostile host brain environment, lessens the effectiveness of this approach. We focused on the effect of oxidative stress against grafted NSCs and hypothesized that conferring antioxidant properties to transplanted NSCs may overcome their death an ...[more]

PMID: 24326392

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Project description:Repetitive transcranial magnetic stimulation (rTMS) is a physical treatment applied during recovery after intracerebral hemorrhage (ICH). With in vivo and in vitro assays, the present study sought to investigate how rTMS influences neural stem cells (NSCs) after ICH and the possible mechanism. Following a collagenase-induced ICH, adult male C57BL/6 J mice were subjected to rTMS treatment every 24 h for 5 days using the following parameters: frequency, 10 Hz; duration, 2 s; wait time, 5.5 s; 960 trains (500 µV/div, 5 ms/div, default setting). Brain water content and neurobehavioral score were assessed at days 1, 3, and 5 after ICH. The proliferation and differentiation of NSCs were observed using immunofluorescence staining for Nestin, Ki-67, DCX, and GFAP on day 3 after ICH, and rTMS treatment with the same parameters was applied to NSCs in vitro. We found that rTMS significantly reduced brain edema and alleviated neural functional deficits. The mice that underwent ICH recovered faster after rTMS treatment, with apparent proliferation and neuronal differentiation of NSCs and attenuation of glial differentiation and GFAP aggregation. Accordingly, proliferation and neuronal differentiation of isolated NSCs were promoted, while glial differentiation was reduced. In addition, microarray analysis, western blotting assays, and calcium imaging were applied to initially investigate the potential mechanism. Bioinformatics showed that the positive effect of rTMS on NSCs after ICH was largely related to the MAPK signaling pathway, which might be a potential hub signaling pathway under the complex effect exerted by rTMS. The results of the microarray data analysis also revealed that Ca2+ might be the connection between physical treatment and the MAPK signaling pathway. These predictions were further identified by western blotting analysis and calcium imaging. Taken together, our findings showed that rTMS after ICH exhibited a restorative effect by enhancing the proliferation and neuronal differentiation of NSCs, potentially through the MAPK signaling pathway.

Project description:BackgroundIntracerebral hemorrhage (ICH) is a major public health concern, and mesenchymal stem cells (MSCs) hold great potential for treating ICH. However, the quantity and quality of MSCs decline in the cerebral niche, limiting the potential efficacy of MSCs. Hypoxic preconditioning is suggested to enhance the survival of MSCs and augment the therapeutic efficacy of MSCs in ICH. MicroRNAs (miRNAs) are known to mediate cellular senescence. However, the precise mechanism by which miRNAs regulate the senescence of hypoxic MSCs remains to be further studied. In the present study, we evaluated whether hypoxic preconditioning enhances the survival and therapeutic effects of olfactory mucosa MSC (OM-MSC) survival and therapeutic effects in ICH and investigated the mechanisms by which miRNA ameliorates hypoxic OM-MSC senescence.MethodsIn the in vivo model, ICH was induced in mice by administration of collagenase IV. At 24 h post-ICH, 5 × 105 normoxia or hypoxia OM-MSCs or saline was administered intracerebrally. The behavioral outcome, neuronal apoptosis, and OM-MSC survival were evaluated. In the in vitro model, OM-MSCs were exposed to hemin. Cellular senescence was examined by evaluating the expressions of P16INK4A, P21, P53, and by β-galactosidase staining. Microarray and bioinformatic analyses were performed to investigate the differences in the miRNA expression profiles between the normoxia and hypoxia OM-MSCs. Autophagy was confirmed using the protein expression levels of LC3, P62, and Beclin-1.ResultsIn the in vivo model, transplanted OM-MSCs with hypoxic preconditioning exhibited increased survival and tissue-protective capability. In the in vitro model, hypoxia preconditioning decreased the senescence of OM-MSCs exposed to hemin. Bioinformatic analysis identified that microRNA-326 (miR-326) expression was significantly increased in the hypoxia OM-MSCs compared with that of normoxia OM-MSCs. Upregulation of miR-326 alleviated normoxia OM-MSC senescence, whereas miR-326 downregulation increased hypoxia OM-MSC senescence. Furthermore, we showed that miR-326 alleviated cellular senescence by upregulating autophagy. Mechanistically, miR-326 promoted the autophagy of OM-MSCs via the PI3K signaling pathway by targeting polypyrimidine tract-binding protein 1 (PTBP1).ConclusionsOur study shows that hypoxic preconditioning delays OM-MSC senescence and augments the therapeutic efficacy of OM-MSCs in ICH by upregulating the miR-326/PTBP1/PI3K-mediated autophagy.

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Transplantation of neural stem cells that overexpress SOD1 enhances amelioration of intracerebral hemorrhage in mice.

Publications

Transplantation of neural stem cells that overexpress SOD1 enhances amelioration of intracerebral hemorrhage in mice.

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