scholarly journals Lentiviral Vectors Delivered with Biomaterials as Therapeutics for Spinal Cord Injury

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2102
Author(s):  
Ciara Shortiss ◽  
Linda Howard ◽  
Siobhan S. McMahon
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Lentiviral Vectors ◽  
Therapeutic Effects ◽  
Nucleic Acid Delivery ◽  
Permanent Disability ◽  
Cord Injury ◽  
Socioeconomic Burden ◽  
Superior Approach

Spinal cord injury (SCI) is a devastating trauma that can cause permanent disability, life-long chronic issues for sufferers and is a big socioeconomic burden. Regenerative medicine aims to overcome injury caused deficits and restore function after SCI through gene therapy and tissue engineering approaches. SCI has a multifaceted pathophysiology. Due to this, producing therapies that target multiple different cellular and molecular mechanisms might prove to be a superior approach in attempts at regeneration. Both biomaterials and nucleic acid delivery via lentiviral vectors (LVs) have proven to promote repair and restoration of function post SCI in animal models. Studies indicate that a combination of biomaterials and LVs is more effective than either approach alone. This review presents studies supporting the use of LVs and LVs delivered with biomaterials in therapies for SCI and summarises methods to combine LVs with biomaterials for SCI treatment. By summarising this knowledge this review aims to demonstrate how LV delivery with biomaterials can augment/compliment both LV and biomaterial therapeutic effects in SCI.

scholarly journals Retrograde Activation of the Extrinsic Apoptotic Pathway in Spinal-Projecting Neurons after a Complete Spinal Cord Injury in Lampreys

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Antón Barreiro-Iglesias ◽  
Daniel Sobrido-Cameán ◽  
Michael I. Shifman
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Extrinsic Pathway ◽  
Apoptotic Pathway ◽  
Permanent Disability ◽  
Descending Neurons ◽  
Neuronal Soma ◽  
Cord Injury ◽  
Complete Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition that leads to permanent disability because injured axons do not regenerate across the trauma zone to reconnect to their targets. A prerequisite for axonal regeneration will be the prevention of retrograde degeneration that could lead to neuronal death. However, the specific molecular mechanisms of axotomy-induced degeneration of spinal-projecting neurons have not been elucidated yet. In lampreys, SCI induces the apoptotic death of identifiable descending neurons that are “bad regenerators/poor survivors” after SCI. Here, we investigated the apoptotic process activated in identifiable descending neurons of lampreys after SCI. For this, we studied caspase activation by using fluorochrome-labeled inhibitors of caspases, the degeneration of spinal-projecting neurons using Fluro-Jade C staining, and the involvement of the intrinsic apoptotic pathway by means of cytochrome c and Vαdouble immunofluorescence. Our results provide evidence that, after SCI, bad-regenerating spinal cord-projecting neurons slowly degenerate and that the extrinsic pathway of apoptosis is involved in this process. Experiments using the microtubule stabilizer Taxol showed that caspase-8 signaling is retrogradely transported by microtubules from the site of axotomy to the neuronal soma. Preventing the activation of this process could be an important therapeutic approach after SCI in mammals.

scholarly journals Exosomes derived from miR-26a-modified MSCs promote axonal regeneration via the PTEN/AKT/mTOR pathway following spinal cord injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuyong Chen ◽  
Zhenming Tian ◽  
Lei He ◽  
Can Liu ◽  
Nangxiang Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Axonal Regeneration ◽  
Molecular Mechanisms ◽  
Diffusion Tensor ◽  
Motor Evoked Potential ◽  
Mtor Pathway ◽  
Histological Evaluation ◽  
Therapeutic Effects ◽  
Cord Injury

Abstract Background Exosomes derived from the bone marrow mesenchymal stem cell (MSC) have shown great potential in spinal cord injury (SCI) treatment. This research was designed to investigate the therapeutic effects of miR-26a-modified MSC-derived exosomes (Exos-26a) following SCI. Methods Bioinformatics and data mining were performed to explore the role of miR-26a in SCI. Exosomes were isolated from miR-26a-modified MSC culture medium by ultracentrifugation. A series of experiments, including assessment of Basso, Beattie and Bresnahan scale, histological evaluation, motor-evoked potential recording, diffusion tensor imaging, and western blotting, were performed to determine the therapeutic influence and the underlying molecular mechanisms of Exos-26a in SCI rats. Results Exos-26a was shown to promote axonal regeneration. Furthermore, we found that exosomes derived from miR-26a-modified MSC could improve neurogenesis and attenuate glial scarring through PTEN/AKT/mTOR signaling cascades. Conclusions Exosomes derived from miR-26a-modified MSC could activate the PTEN-AKT-mTOR pathway to promote axonal regeneration and neurogenesis and attenuate glia scarring in SCI and thus present great potential for SCI treatment. Graphical abstract

Transplantation Strategies for Spinal Cord Injury Based on Microenvironment Modulation

2020 ◽  
Vol 15 (6) ◽  
pp. 522-530
Author(s):  
Jiawei Shu ◽  
Feng Cheng ◽  
Zhe Gong ◽  
Liwei Ying ◽  
Chenggui Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Autonomic Dysfunction ◽  
Peripheral Nerve Injury ◽  
Therapeutic Effects ◽  
Permanent Damage ◽  
Cord Injury ◽  
Severe Motor

Spinal cord injury (SCI) is different from peripheral nerve injury; it results in devastating and permanent damage to the spine, leading to severe motor, sensory and autonomic dysfunction. SCI produces a complex microenvironment that can result in hemorrhage, inflammation and scar formation. Not only does it significantly limit regeneration, but it also challenges a multitude of transplantation strategies. In order to promote regeneration, researchers have recently begun to focus their attention on strategies that manipulate the complicated microenvironment produced by SCI. And some have achieved great therapeutic effects. Hence, reconstructing an appropriate microenvironment after transplantation could be a potential therapeutic solution for SCI. In this review, first, we aim to summarize the influential compositions of the microenvironment and their different effects on regeneration. Second, we highlight recent research that used various transplantation strategies to modulate different microenvironments produced by SCI in order to improve regeneration. Finally, we discuss future transplantation strategies regarding SCI.

scholarly journals AAV2-mediated and hypoxia response element-directed expression of bFGF in neural stem cells showed therapeutic effects on spinal cord injury in rats

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Sipin Zhu ◽  
Yibo Ying ◽  
Jiahui Ye ◽  
Min Chen ◽  
Qiuji Wu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Clinical Trials ◽  
Control Group ◽  
Therapeutic Effects ◽  
Hypoxia Response Element ◽  
Neurofilament Protein ◽  
Response Element ◽  
Hypoxia Response ◽  
Cord Injury

AbstractNeural stem cell (NSCs) transplantation has been one of the hot topics in the repair of spinal cord injury (SCI). Fibroblast growth factor (FGF) is considered a promising nerve injury therapy after SCI. However, owing to a hostile hypoxia condition in SCI, there remains a challenging issue in implementing these tactics to repair SCI. In this report, we used adeno-associated virus 2 (AAV2), a prototype AAV used in clinical trials for human neuron disorders, basic FGF (bFGF) gene under the regulation of hypoxia response element (HRE) was constructed and transduced into NSCs to yield AAV2-5HRE-bFGF-NSCs. Our results showed that its treatment yielded temporally increased expression of bFGF in SCI, and improved scores of functional recovery after SCI compared to vehicle control (AAV2-5HRE-NSCs) based on the analyses of the inclined plane test, Basso–Beattie–Bresnahan (BBB) scale and footprint analysis. Mechanistic studies showed that AAV2-5HRE-bFGF-NSCs treatment increased the expression of neuron-specific neuronal nuclei protein (NeuN), neuromodulin GAP43, and neurofilament protein NF200 while decreased the expression of glial fibrillary acidic protein (GFAP) as compared to the control group. Further, the expressions of autophagy-associated proteins LC3-II and Beclin 1 were decreased, whereas the expression of P62 protein was increased in AAV2-5HRE-bFGF-NSCs treatment group. Taken together, our data indicate that AAV2-5HRE-bFGF-NSCs treatment improved the recovery of SCI rats, which is accompanied by evidence of nerve regeneration, and inhibition of SCI-induced glial scar formation and cell autophagy. Thus, this study represents a step forward towards the potential use of AAV2-5HRE-bFGF-NSCs for future clinical trials of SCI repair.

scholarly journals Therapeutic Effects of Traditional Chinese Medicine on Spinal Cord Injury: A Promising Supplementary Treatment in Future

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Qian Zhang ◽  
Hao Yang ◽  
Jing An ◽  
Rui Zhang ◽  
Bo Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Epigallocatechin Gallate ◽  
Therapeutic Effects ◽  
Cord Injury ◽  
Supplementary Treatment ◽  
Natural Drugs ◽  
Doctoral Dissertations

Objective. Spinal cord injury (SCI) is a devastating neurological disorder caused by trauma. Pathophysiological events occurring after SCI include acute, subacute, and chronic phases, while complex mechanisms are comprised. As an abundant source of natural drugs, Traditional Chinese Medicine (TCM) attracts much attention in SCI treatment recently. Hence, this review provides an overview of pathophysiology of SCI and TCM application in its therapy.Methods. Information was collected from articles published in peer-reviewed journals via electronic search (PubMed, SciFinder, Google Scholar, Web of Science, and CNKI), as well as from master’s dissertations, doctoral dissertations, and Chinese Pharmacopoeia.Results. Both active ingredients and herbs could exert prevention and treatment against SCI, which is linked to antioxidant, anti-inflammatory, neuroprotective, or antiapoptosis effects. The detailed information of six active natural ingredients (i.e., curcumin, resveratrol, epigallocatechin gallate, ligustrazine, quercitrin, and puerarin) and five commonly used herbs (i.e., Danshen, Ginkgo, Ginseng, Notoginseng, and Astragali Radix) was elucidated and summarized.Conclusions. As an important supplementary treatment, TCM may provide benefits in repair of injured spinal cord. With a general consensus that future clinical approaches will be diversified and a combination of multiple strategies, TCM is likely to attract greater attention in SCI treatment.

scholarly journals The effectiveness and safety of LMWH for preventing thrombosis in patients with spinal cord injury: a meta-analysis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ze Lin ◽  
Yun Sun ◽  
Hang Xue ◽  
Lang Chen ◽  
Chenchen Yan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Venous Thrombosis ◽  
Meta Analysis ◽  
Therapeutic Effects ◽  
Significant Difference ◽  
Cord Injury ◽  
Review Manager ◽  
Evident Difference

Abstract Background Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are commonly used for preventing venous thrombosis of the lower extremity in patients with traumatic spinal cord injury. Although, LMWH is the most commonly used drug, it has yet to be established whether it is more effective and safer than UFH. Further, a comparison of the effectiveness of LMWH in preventing thrombosis at different locations and different degrees of spinal cord injury has also not been clearly defined. Materials and methods Cohort studies comparing the use of LMWH and UFH in the prevention of lower limb venous thrombosis in patients with spinal cord injury were identified using PubMed. The risk of bias and clinical relevance of the included studies were assessed using forest plots. The Newcastle-Ottawa quality assessment scale was used to evaluate the quality of the included studies. The main results of the study were analyzed using Review Manager 5.3. Results A total of five studies were included in this meta-analysis. Four studies compared the effectiveness and safety of LMWH and UFH in preventing thrombosis in patients with spinal cord injury. No significant differences were found between the therapeutic effects of the two drugs, and the summary RR was 1.33 (95% CI 0.42–4.16; P = 0.63). There was also no significant difference in the risk of bleeding between the two medications, and the aggregate RR was 0.78 (95% CI 0.55–1.12; P = 0.18). When comparing the efficacy of LMWH in preventing thrombosis in different segments and different degrees of spinal cord injury, no significant differences were found. Conclusions The results of this analysis show that compared with UFH, LMWH has no obvious advantages in efficacy nor risk prevention, and there is no evident difference in the prevention of thrombosis for patients with injuries at different spinal cord segments.

scholarly journals Therapeutic effects of vitamin D3 on motor functions following experimental spinal cord injury

2015 ◽  
Vol 21 (2) ◽  
pp. 55-61 ◽  
Author(s):  
Hasan Çelik ◽  
Senem Mutevelizade ◽  
Ferhat Harman ◽  
Gökhan Yılmaz ◽  
Mehmet Zafer Berkman
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Vitamin D3 ◽  
Therapeutic Effects ◽  
Motor Functions ◽  
Experimental Spinal Cord Injury ◽  
Cord Injury

scholarly journals Exendin-4 improves neuron protection and functional recovery in experimental spinal cord injury in rats through regulating PCBP2 expression

2020 ◽  
Author(s):  
Huaichao Luo ◽  
Qingwei Wang ◽  
Lei Wang
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cell Apoptosis ◽  
Sham Group ◽  
Sham Operation ◽  
Therapeutic Effects ◽  
Rat Models ◽  
Apoptosis Rate ◽  
Cord Injury ◽  
Group A

AbstractAimsIn the present research, we assessed the therapeutic effects of Exendin-4 (Ex-4) on rat models with spinal cord injury (SCI).Materials and methods36 male Sprague–Dawley rats were randomly allocated into three groups, including sham operation group, SCI group and SCI+Ex-4 group (Ex-4 treatment (10 µg/rat) after SCI, i.p.). In the SCI group, a laminectomy was performed at the T10 vertebrae, followed by weight-drop contusion of the spinal cord. In the sham group, a laminectomy was carried out without SCI contusion.Key findingsOur results showed that Basso-Beattie-Bresnahan scale scores were significantly decreased after SCI, and were obviously improved in SCI rats with Ex-4 administration. Additionally, the water content of spinal cord in SCI group was dramatically increased than that in sham group, and after Ex-4 treatment, degree of edema of spinal cord was remarkably reduced. And also, concentration levels of inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α) in the spinal cord were significantly elevated after SCI, and were remarkably reduced in SCI rats with Ex-4 administration. Subsequently, cell apoptosis rate in the injured spinal cord was significantly increased, and after Ex-4 treatment, cell apoptosis rate was remarkably decreased. We also revealed that levels of PCBP2 mRNA and protein were significantly up-regulated after SCI, and were dramatically dropped in SCI rats with Ex-4 administration.SignificanceTake altogether, our findings disclosed that Ex-4 plays a role in promoting neurological function recovery and inhibiting neuronal apoptosis through effecting PCBP2 expression in SCI rat models.

Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway

2019 ◽  
Author(s):  
Zhou Zhilai ◽  
Tian Xiaobo ◽  
Mo Biling ◽  
Xu Huali ◽  
Yao Shun ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
Therapeutic Effects ◽  
Mesenchymal Stem Cell Transplantation ◽  
Cord Injury

Abstract Background The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression.Methods Using a mouse model of compression SCI, ADSCs and Jagged1 small interfering RNA (siRNA) were injected into the spinal cord. Locomotor function, spinal cord tissue morphology and the levels of various proteins and transcripts were compared between groups.Results ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium binding adapter molecule 1 (Iba1) and ED1 staining in the injured spinal cord, promoting the survival of neurons. These changes were accompanied by improved functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in a decrease in SCI-induced proinflammatory cytokines as well as the activation of microglia. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 following SCI.Conclusion The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation.

Activation of SIRT1 by Hyperbaric  Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

2020 ◽  
Author(s):  
Huiqiang Chen ◽  
Mengyu Yao ◽  
Zhibo Li ◽  
Ranran Xing ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Hyperbaric Oxygenation ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Sprague Dawley ◽  
Inflammatory Cascade ◽  
Locomotor Function ◽  
Cord Injury

Abstract Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

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