Neural Stem Cells Genetically Modified to Overexpress Cu/Zn-Superoxide Dismutase Enhance Amelioration of Ischemic Stroke in Mice

Abstract

Background and Purpose The harsh host brain microenvironment caused by production of reactive oxygen species after ischemic reperfusion injury offers a significant challenge to survival of transplanted neural stem cells (NSCs) after ischemic stroke. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. Here, we have investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted stem cells and accelerates amelioration of ischemic stroke. Methods NSCs genetically modified to overexpress or downexpress SOD1 were administered intracerebrally 2 days after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from Days 0 to 28 after stroke. Results Overexpression of SOD1 suppressed production of superoxide anions after ischemic reperfusion injury and reduced NSC death after transplantation. In contrast, downexpression of SOD1 promoted superoxide generation and increased oxidative stress-mediated NSC death. Transplantation of SOD1-overexpressing NSCs enhanced angiogenesis in the ischemic border zone through up-regulation of vascular endothelial growth factor. Moreover, grafted SOD1-overexpressing NSCs reduced infarct size and improved behavioral performance, compared with NSCs that were not genetically modified. Conclusions Our findings reveal a strong involvement of SOD1 expression in NSC survival after ischemic reperfusion injury. We propose that conferring antioxidant properties on NSCs by genetic manipulation of SOD1 is a potential approach for enhancing the effectiveness of cell transplantation therapy in ischemic stroke.

Cell based therapies for ischemic stroke: From basic science to bedside

“…A variety of genes was pre-incorporated into the implanted cells and has been reported to induce greater functional recovery. These therapeutic genes include angiogenic factors like VEGF (Zhu et al, 2005), Ang-1 (Onda et al, 2008), HGF (Zhao et al, 2006), PIGF (Liu et al, 2006), neurotrophic factors like BDNF (van Velthoven et al, 2013; Kurozumi et al, 2004; Chang et al, 2013a), ciliary neurotrophic factor (CNTF) (Kurozumi et al, 2005), NGF (Andsberg et al, 1998), GDNF (Kurozumi et al, 2005; Chen et al, 2009; Horita et al, 2006; Ou et al, 2010), neurotrophin-3 (NT-3) (Park et al, 2006), Neurogenin 1 (Kim et al, 2008), and other genes like survivin (Liu et al, 2011), Noggin (Chen et al, 2011a; Ding et al, 2011), copper/zinc-superoxide dismutase (Sakata et al, 2012) and CXCR4 (Yu et al, 2012). Some investigators further tried to transfect multiple genes into cells ex vivo and examine the potential therapeutic benefits of the synergistic effects (Ding et al, 2011; Toyama et al, 2009).…”

Stem Cell–Based Tissue Replacement After Stroke

“…To augment the growth factor-mediated neuroprotective potential of NSCs, therapeutic approaches that employ the induced overexpression of factors such as BDNF 63 for the treatment of ischemic stroke, or GDNF 64 for hemorrhagic stroke, have been suggested. These strategies can even be combined with the use of cytoprotectants, making transplanted NSCs more resilient against oxidative stress and reperfusion injury 65, 66 . In all these cases, permanent survival of the graft is not a necessary condition to elicit the beneficial effect.…”

Vasculogenesis in Experimental Stroke After Human Cerebral Endothelial Cell Transplantation

“…1–4 However, a major gap in our knowledge is the mechanism of action underlying stem cell therapy. Cell transplantation studies in stroke have mostly focused on neuronal stem or progenitor cells as donor cell type, 5–15 primarily to replace the dead or injured neuronal cells of the stroke brain. Indeed, such transplantation of neuronal stem or progenitor cells has resulted in neurogenesis with reported functional recovery in transplanted stroke animals.…”