Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is inv...Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord barrier.In this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in rats.Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ry.Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein.Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury,as shown by the immunofluorescence of an endothelial cell marker(rat endothelium cell antigen-1,RECA-1) and fe rroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase.Liproxstatin-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and 15-lipoxygenase.Furthermore,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment.In summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.展开更多
Spinal cord injury(SCI)causes motor,sensory and automatic impairment due to rarely axon regeneration.Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal rege...Spinal cord injury(SCI)causes motor,sensory and automatic impairment due to rarely axon regeneration.Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal regenerative ability and disconnection of neural elements after injury,as well as the limited systemic drug delivery efficiency caused by blood spinal cord barrier.To develop an effective non-invasive treatment strategy for SCI in clinic,we generated an autologous plasma exosome(AP-EXO)based biological scaffold where AP-EXO was loaded with neuron targeting peptide(RVG)and growth-facilitating peptides(ILP and ISP).This scaffold can be targeted delivered to neurons in the injured area and elicit robust axon regrowth across the lesion core to the levels over 30-fold greater than naïve treatment,thus reestablish the intraspinal circuits and promote motor functional recovery after spinal cord injury in mice.More importantly,in ex vivo,human plasma exosomes(HP-EXO)loaded with combinatory peptides of RVG,ILP and ISP showed safety and no liver and kidney toxicity in the application to nude SCI mice.Combining the efficacy and safety,the AP-EXO-based personalized treatment confers functional recovery after SCI and showed immense promising in biomedical applications in treating SCI.It is helpful to expand the application of combinatory peptides and human plasma derived autologous exosomes in promoting regeneration and recovery upon SCI treatment.展开更多
基金National Natural Science Foundation of China,No.81972074 (to XY)Natural Science Foundation of Tianjin,No.19JCZDJC34900 (to XY)National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100 (to SF)。
文摘Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord barrier.In this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in rats.Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ry.Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein.Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury,as shown by the immunofluorescence of an endothelial cell marker(rat endothelium cell antigen-1,RECA-1) and fe rroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase.Liproxstatin-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and 15-lipoxygenase.Furthermore,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment.In summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.
基金This work was supported by the National Key Research and Development Project of Stem Cell and Transformation Research(2019YFA0112100),ChinaNational Natural Science Foundation of China(81930070)+3 种基金National Natural Science Foundation of China(82102560)the Natural Science Foundation of Shandong Province,China(ZR2021QH097)the No.69 General Fund of China Postdoctoral Science Foundation(2021M691936)Talent project of Shandong University(22480082063100),China.
文摘Spinal cord injury(SCI)causes motor,sensory and automatic impairment due to rarely axon regeneration.Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal regenerative ability and disconnection of neural elements after injury,as well as the limited systemic drug delivery efficiency caused by blood spinal cord barrier.To develop an effective non-invasive treatment strategy for SCI in clinic,we generated an autologous plasma exosome(AP-EXO)based biological scaffold where AP-EXO was loaded with neuron targeting peptide(RVG)and growth-facilitating peptides(ILP and ISP).This scaffold can be targeted delivered to neurons in the injured area and elicit robust axon regrowth across the lesion core to the levels over 30-fold greater than naïve treatment,thus reestablish the intraspinal circuits and promote motor functional recovery after spinal cord injury in mice.More importantly,in ex vivo,human plasma exosomes(HP-EXO)loaded with combinatory peptides of RVG,ILP and ISP showed safety and no liver and kidney toxicity in the application to nude SCI mice.Combining the efficacy and safety,the AP-EXO-based personalized treatment confers functional recovery after SCI and showed immense promising in biomedical applications in treating SCI.It is helpful to expand the application of combinatory peptides and human plasma derived autologous exosomes in promoting regeneration and recovery upon SCI treatment.
