Effects of over-expression of HIF-1alpha in bone marrow-derived mesenchymal stem cells on traumatic brain injury

Abstract

Mesenchymal stem cells (MSCs) have been shown to play therapeutic effect in traumatic brain injury (TBI). To augment the therapeutic effect, MSCs could be engineered to over-express genes that are beneficial for treatment. In the present study, we over-expressed hypoxia inducible factor (HIF)-1alpha in bone marrow derived MSCs (BM-MSCs) and sought to investigate whether HIF-1alpha could enhance the therapeutic effect of MSCs in a mouse model of TBI. Balb/c mice were subjected to controlled cortical impact injury and MSCs were transplanted intravenously at 6 h after injury. The lesion volume and brain water content were measured and the neurological function was assessed by modified neurologic severity score tests. Double-labeled immunofluorescence for BrdU and NeuU was performed to determine angiogenesis and neurogenesis. The expression of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) was measured by quantitative RT-PCR and western blotting. After TBI, mice received BM-MSCs over-expressing HIF-1alpha showed significantly more functional recovery, reduced brain damage, increased angiogenesis and neurogenesis and increased expression of VEGF and EPO, compared with control mice or mice treated with non-transduced BM-MSCs. Over-expression of HIF-1alpha enhanced BM-MSCs induced improvement of neurological recovery after TBI, by stimulating angiogenesis and neurogenesis.