Effects of transplantation with bone marrow-derived mesenchymal stem cells modified by Survivin on experimental stroke in rats

Abstract

BackgroundThis study was performed to determine whether injury induced by cerebral ischemia could be further improved by transplantation with bone marrow-derived mesenchymal stem cells (MSCs) modified by Survivin (SVV).MethodsMSCs derived from bone marrow of male Sprague-Dawley rats were infected by the self-inactive lentiviral vector GCFU carrying green fluorescent protein (GFP) gene and SVV recombinant vector (GCFU-SVV). In vitro, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were detected in infected MSCs supernatants under hypoxic conditions by ELSIA. In vivo, experiments consisted of three groups, one receiving intravenous injection of 500 μl of phosphate-buffered saline (PBS) without cells (control group) and two groups administered the same volume solution with either three million GFP-MSCs (group GFP) or SVV/GFP-MSCs (group SVV). All animals were submitted to 2-hour middle cerebral artery occlusion (MCAO) and then reperfusion. Differentiation and survival of the transplanted MSCs were determined by confocal microscope. Western blot was used to detect the expression of VEGF and bFGF in ischemic tissue. A 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to assess the infarct volume. Evaluation of neurological function was performed using a modified Neurological Severity Score (mNSS).ResultsIn vitro, modification with SVV further increased secretion of VEGF and bFGF under hypoxic condition. In vivo, only very few transplantated cells co-expressed GFP and NeuN. The survival transplanted cells in the group SVV was 1.3-fold at 4 days after transplantation and 3.4-fold higher at 14 days after transplantation, respectively, when compared with group GFP. Expression of VEGF and bFGF in the ischemic tissue were further up-regulated by modification with SVV. Moreover, modification with SVV further reduced the cerebral infarct volume by 5.2% at 4 days after stroke and improved post-stroke neurological function at 14 days after transplantation.ConclusionModification with SVV could further enhance the therapeutic effects of MSCs possibly through improving the MSCs survival capacity and up-regulating the expression of protective cytokines in the ischemic tissue.

Protective effect of berberine against oxidative stress-induced apoptosis in rat bone marrow-derived mesenchymal stem cells

“…Owing to the low immunogenicity and transplantability (32), BMSCs are an effective resource for transplantation in clinical application, with the establishment of cell banks for bone regenerative medicine (2,33). Previously, much attention has been directed towards the poor survival of transplantation in MSC-based therapy (5,9,34,35). For basic and clinician scientists, it is necessary to utilize strategies to improve low cell survival rates.…”

Genetic modification of mesenchymal stem cells in spinal cord injury repair strategies

“…Many molecules have been recognized for their promising and potent activities of rescuing SCI. Besides the above-mentioned neurotrophic factors, TrkC, and HGF, other cytokines and anti-apoptosis molecules can also be used to modify MSCs, such as D15A (with NT-3 and BDNF activity) (54), ciliary neurotrophic factor (CNTF) (55), and survivin (56). In the future, more molecules acting as overexpressing genes in MSCs and treating SCI will be recognized.…”

Mesenchymal stem cell-based therapy for ischemic stroke

“…Many, but not all, of these studies reported MSCs reduced infarct size and induced functional recovery as reported by lessening of motor deficits or special learning as measured by the radial maze test [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Many of these studies report a lowering of deficits as assessed by the composite modified neurological severity score (mNSS), while others demonstrated reduced inflammation and apoptosis, as well as increased neurite outgrowth and plasticity [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Interestingly, recent studies have also determined that exosomes secreted by MSCs are capable of inducing functional recovery in models of ischemic stroke [24,41,47,55,58].…”