Intravenous administration of glial cell line‐derived neurotrophic factor gene‐modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat

Abstract

Intravenous administration of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Several hypotheses to account for these therapeutic effects have been suggested, and current thinking is that neuroprotection rather than neurogenesis is responsible. To enhance the therapeutic benefits of hMSCs potentially, we transfected hMSCs with the glial cell line-derived neurotrophic factor (GDNF) gene using a fiber-mutant F/RGD adenovirus vector and investigated whether GDNF genemodified hMSCs (GDNF-hMSCs) could contribute to functional recovery in a rat permanent middle cerebral artery occlusion (MCAO) model. We induced MCAO by using intraluminal vascular occlusion, and GDNF-hMSCs were intravenously infused into the rats 3 hr later. MRI and behavioral analyses revealed that rats receiving GDNF-hMSCs or hMSCs exhibited increased recovery from ischemia compared with the control group, but the effect was greater in the GDNF-hMSC group. Thus, these results suggest that intravenous administration of hMSCs transfected with the GDNF gene using a fiber-mutant adenovirus vector may be useful in the cerebral ischemia and may represent a new strategy for the treatment of stroke. Keywords bone marrow; stroke; transplantationTransplantation of bone marrow-derived mesenchymal stem cells (MSCs) has been reported to reduce infarction size and ameliorate functional deficits in rodent cerebral ischemia models (Chen et al., 2001;Iihoshi et al., 2004;Nomura et al., 2005;Honma et al., 2006). Indeed, MSCs derived from adult human bone marrow (hMSCs) have been shown to secrete trophic factors,including glial cell line-derived neurotrophic factor (GDNF), brain-derived Chen et al., 2002;Iihoshi et al., 2004;Kurozumi et al., 2005;Nomura et al., 2005). Moreover, transplantation of hMSCs modified to hypersecrete BDNF has a greater therapeutic effect in cerebral ischemia models than transplantation of nongene-modified hMSCs (Kurozumi et al., 2004(Kurozumi et al., , 2005Nomura et al., 2005). Thus, the release of trophic factors from transplanted MSCs within the host brain may contribute to the reduction in infarction size and to the increased functional recovery following ischemia in recipient animals.GDNF, a distantly related member of the transforming growth factor-β superfamily, is a potent neurotrophic factor that promotes neuronal survival and differentiation (Beck et al., 1995;Tomac et al., 1995;Oppenheim et al., 1995;Yan et al., 1995;Liberatore et al., 1997) and becomes expressed in the ischemic brain (Abe and Hayashi, 1997;Zhang et al., 2002). Moreover, surface application and intracerebral administration of GDNF decreased cerebral infarction volume (Wang et al., 1997;Kitagawa et al., 1998;Zhang et al., 2002). Direct intracerebral injection of hMSCs transfected with the GDNF gene (GDNF-hMSCs) resulted in therapeutic benefits in a rat middle cerebral artery occlusion (MCAO) model (Kurozumi et al., 2005).Although direct intracere...

Human neural stem cells overexpressing glial cell line-derived neurotrophic factor in experimental cerebral hemorrhage

“…[24][25][26][27][28][29]43,44 It should be noted that repeated administration of GDNF through intracerebral or intraventricular space is required in experimental animals to sustain neuroprotective and neurotrophic activity as the beneficial effects of GDNF is transient and short lived. 45 For this reason, brain transplantation of human NSCs genetically modified to carry GDNF gene in ICH or other neurological diseases or injury is a highly effective strategy to deliver GDNF steadily and for a long time in the lesion sites. In this study, the GDNF level in the ICH brain loci with F3.GDNF grafts at 8 weeks post-transplantation was 258 pg per mg protein as compared with 315 pg per mg protein at 2 weeks post-transplantation indicating that the GDNF levels in the ICH loci were maintained in relatively high levels for as long as 8 weeks after transplantation (Figure 1d).…”

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

“…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.…”

Hypoxic and ischemic effects on gene and protein expression levels of paracrine factors by human olfactory mucosa mesenchymal-like stem cells

“…Moreover, the ischemic conditions present after cerebral ischemia include both hypoxia and serum deprivation. 22 Reduction in serum levels reduces cell proliferation and upregulates genes for angiogenic factors and endothelial differentiation in MSCs. 23 Serum deprivation changes the expression of endothelial markers and the secretion of paracrine factors in MSCs.…”