I.v. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat

Abstract

Abstract-I.v. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

Subchronic Alpha-Linolenic Acid Treatment Enhances Brain Plasticity and Exerts an Antidepressant Effect: A Versatile Potential Therapy for Stroke

“…Research activities focusing on NSC have shown that promoting their proliferation or grafting/infusing them by different routes into the brain leads to neurological improvement in different brain disease models, including stroke (Nomura et al, 2005;Pallini et al, 2005;Capone et al, 2007;Maysami et al, 2008). This benefit does not come only by their capacity to replace lost neurons.…”

Migration, fate and in vivo imaging of adult stem cells in the CNS

“…47,48 Human MSCs were injected into rats after middle cerebral artery occlusion. 49,50 In both studies, implanted cells reduced the lesion volume and elicited functional improvement compared with the control sham group. As MSCs can be easily genetically modified, numerous studies in which MSCs overexpress some bioactive molecules have appeared.…”

“…As MSCs can be easily genetically modified, numerous studies in which MSCs overexpress some bioactive molecules have appeared. [50][51][52] Human MSCs expressing brain-derived neurotrophic factor or human MSCs producing placental growth factor have an enhanced effect on functional outcome and lesion volume compared to human MSCs alone, suggesting the use of human MSCs as vehicles for the delivery of growth factors. As MSC-based treatments for brain disorders have advanced rapidly, the visualization of implanted stem cells in experimental models of brain disorders is at the leading edge of potential applications of MRI.…”

Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model

“…Each rat was placed in an animal holder/MRI probe apparatus and positioned inside the magnet (Liu et al, 2006;Nomura et al, 2005). The animal's head was held in place inside the RF coil.…”