Therapeutic Effect of BDNF-Overexpressing Human Neural Stem Cells (HB1.F3.BDNF) in a Rodent Model of Middle Cerebral Artery Occlusion

Abstract

Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) represents the major type of stroke; however, there are still very limited therapeutic options for the stroke-damaged patients. In this study, we evaluated the neurogenic and therapeutic potentials of human neural stem cells (NSCs) overexpressing brain-derived neurotrophic factor (HB1.F3.BDNF) following transplantation into a rodent model of MCAo. F3.BDNF human NSCs (F3.BDNF) were transplanted into the contralateral side of striatum at 7 days after MCAo, and the transplanted animals were monitored up to 8 weeks using animal MRI and various behavioral tests before they were sacrificed for immunohistochemical analysis. Interestingly, animal MRI results indicate that the majority of contralaterally transplanted neural stem cells were migrated to the peri-infarct area, showing a pathotropism. Transplanted animals exhibited significant behavioral improvements in stepping, rotarod, and modified neurological severity score (mNSS) tests. We also found that the transplanted human cells were colocalized with nestin, DCX, MAP2, DARPP-32, TH, GAD65/67-positive cells, of which results can be correlated with neural regeneration and behavioral recovery in the transplanted animals. More importantly, we were able to detect high levels of human BDNF protein expression, presumably derived from the transplanted F3.BDNF. Taken together, these results provide strong evidence that human neural stem cells (F3.BDNF) are effective in treating stroke animal models.

Circulating brain derived neurotrophic factor (BDNF) and frequency of BDNF positive T cells in peripheral blood in human ischemic stroke: Effect on outcome

“…For those subjects who do not produce high levels of these cells, we suggest that enhancing this response could beneficial, possibly as a means of delivering BDNF to the site of injury. Other studies that support the role of BDNF in recovery after stroke showed that BDNF-expressing neural stem cells were beneficial (Chang et al, 2013), as were mesenchymal stem cells (Jeong et al, 2014). Methods such as the use of histone deacetylase inhibitors (Kim et al, 2009) or a CD28 superagonist, as have already been shown to be beneficial in experimental stroke (Na et al, 2015), are possible strategies to increase the number of Treg cells.…”

Early neuroprotective effect with lack of long-term cell replacement effect on experimental stroke after intra-arterial transplantation of adipose-derived mesenchymal stromal cells

“…For functional tests, we used the rotarod test and the modified neurological severity score (mNSS) test, as described previously [26]. For the rotarod test, rats were pre-trained under the same conditions three times a day, for 3 consecutive days, before MCAo induction to reduce variation among animals.…”

Stem Cell–Based Tissue Replacement After Stroke

“…GDNF has been reported to be neuroprotective 62 by promoting cell survival, but also enhances axonal outgrowth and synaptogenesis. 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 .…”