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Transplantation of vascular endothelial growth factor-modified neural stem/progenitor cells promotes the recovery of neurological function following hypoxic-ischemic brain damage.

ABSTRACT: Neural stem/progenitor cell (NSC) transplantation has been shown to effectively improve neurological function in rats with hypoxic-ischemic brain damage. Vascular endothelial growth factor (VEGF) is a signaling protein that stimulates angiogenesis and improves neural regeneration. We hypothesized that transplantation of VEGF-transfected NSCs would alleviate hypoxic-ischemic brain damage in neonatal rats. We produced and transfected a recombinant lentiviral vector containing the VEGF165 gene into cultured NSCs. The transfected NSCs were transplanted into the left sensorimotor cortex of rats 3 days after hypoxic-ischemic brain damage. Compared with the NSCs group, VEGF mRNA and protein expression levels were increased in the transgene NSCs group, and learning and memory abilities were significantly improved at 30 days. Furthermore, histopathological changes were alleviated in these animals. Our findings indicate that transplantation of VEGF-transfected NSCs may facilitate the recovery of neurological function, and that its therapeutic effectiveness is better than that of unmodified NSCs.

SUBMITTER: Yao Y

PROVIDER: S-EPMC5090849 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Transplantation of vascular endothelial growth factor-modified neural stem/progenitor cells promotes the recovery of neurological function following hypoxic-ischemic brain damage.

Yao Yue Y Zheng Xiang-Rong XR Zhang Shan-Shan SS Wang Xia X Yu Xiao-He XH Tan Jie-Lu JL Yang Yu-Jia YJ

Neural regeneration research 20160901 9

Neural stem/progenitor cell (NSC) transplantation has been shown to effectively improve neurological function in rats with hypoxic-ischemic brain damage. Vascular endothelial growth factor (VEGF) is a signaling protein that stimulates angiogenesis and improves neural regeneration. We hypothesized that transplantation of VEGF-transfected NSCs would alleviate hypoxic-ischemic brain damage in neonatal rats. We produced and transfected a recombinant lentiviral vector containing the VEGF<sub>165</sub ...[more]

PMID: 27857750

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Project description:BackgroundTransradial catheterization is associated with radial artery injury and vasomotor dysfunction and represents an accessible model of acute vascular injury in humans. We characterized vascular injury and functional recovery to understand the role of circulating endothelial progenitor cells in vascular repair.Methods and resultsIn 50 patients (aged 64±10 years, 70% male) undergoing transradial cardiac catheterization, radial artery injury was assessed by optical coherence tomography and examination of explanted vascular sheaths. Flow- and nitrate-mediated dilatation of the radial artery was assessed in both arms at baseline, at 24 hours, and at 1, 4, and 12 weeks. Circulating endothelial progenitor cell populations were quantified using flow cytometry. Late endothelial outgrowth colonies were isolated and examined in vitro. Optical coherence tomography identified macroscopic injury in 12 of 50 patients (24%), but endothelial cells (1.9±1.2×104 cells) were isolated from all arterial sheaths examined. Compared with the noncatheterized radial artery, flow-mediated vasodilatation was impaired in the catheterized artery at 24 hours (9.9±4.6% versus 4.1±3.1%, P<0.0001) and recovered by 12 weeks (8.1±4.9% versus 10.1±4.9%, P=0.09). Although the number of CD133+ cells increased 24 hours after catheterization (P=0.02), the numbers of CD34+ cells and endothelial outgrowth colonies were unchanged. Migration of endothelial cells derived from endothelial outgrowth colonies correlated with arterial function before catheterization but was not related to recovery of function following injury.ConclusionsTransradial cardiac catheterization causes endothelial denudation, vascular injury, and vasomotor dysfunction that recover over 12 weeks. Recovery of vascular function does not appear to be dependent on the mobilization or function of endothelial progenitor cells.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT02147119.

Project description:INTRODUCTION:Neonatal hypoxia-ischemic brain damage (HIBD) can lead to serious neuron damage and dysfunction, causing a significant worldwide health problem. bFGF as a protective reagent promotes neuron repair under hypoxia/ischemia (HI). However, how bFGF and downstream molecules were regulated in HI remains elusive. METHODS:We established an in vitro HI model by culturing primary cortical neurons and treated with oxygen-glucose deprivation (OGD). We suppressed the expression of bFGF by using siRNA (small interfering RNA) interference to detect the neuronal morphological changes by immunofluorescence staining. To determine the potential mechanisms regulated by bFGF, the change of downstream molecular including IL-1? was examined in bFGF knockdown condition. IL-1? knockout (KO) rats were generated using CRISPR/Cas9-mediated technologies. We used an accepted rat model of HI, to assess the effect of IL-1? deletion on disease outcomes and carried out analysis on the behavior, histological, cellular, and molecular level. RESULTS:We identified that OGD can induce endogenous expression of bFGF. Both OGD and knockdown of bFGF resulted in reduction of neuron numbers, enlarged cell body and shortened axon length. We found molecules closely related to bFGF, such as interleukin-1? (IL-1?). IL-1? was up-regulated after bFGF interference under OGD conditions, suggesting complex signaling between bFGF and OGD-mediated pathways. We found HI resulted in up-regulation of IL-1? mRNA in cortex and hippocampus. IL-1? KO rats markedly attenuated the impairment of long-term learning and memory induced by HI. Meanwhile, IL-1?-/- (KO, homozygous) group showed better neurite growth and less apoptosis in OGD model. Furthermore, serine/threonine protein kinase (AKT1) mRNA and protein expression was significantly up-regulated in IL-1? KO rats. CONCLUSIONS:We showed that IL-1?-mediated axon regeneration underlie the mechanism of bFGF for the treatment of HIBD in neonatal rats. Results from this study would provide insights and molecular basis for future therapeutics in treating HIBD.

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Transplantation of vascular endothelial growth factor-modified neural stem/progenitor cells promotes the recovery of neurological function following hypoxic-ischemic brain damage.

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Transplantation of vascular endothelial growth factor-modified neural stem/progenitor cells promotes the recovery of neurological function following hypoxic-ischemic brain damage.

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