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Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy.

ABSTRACT: Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-?, IL-1?, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.

SUBMITTER: Rong Y

PROVIDER: S-EPMC6472377 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy.

Rong Yuluo Y Liu Wei W Wang Jiaxing J Fan Jin J Luo Yongjun Y Li Linwei L Kong Fanqi F Chen Jian J Tang Pengyu P Cai Weihua W

Cell death & disease 20190418 5

Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. ...[more]

PMID: 31000697

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Project description:Background: Traumatic spinal cord injury (t-SCI) is a severe injury that has a devastating impact on neurological function. Blood spinal cord barrier (BSCB) destruction following SCI aggravates the primary injury, resulting in a secondary injury. A series of experimental treatments have been proven to alleviate BSCB destruction after t-SCI. Methods: From a screen of 1,189 papers, which were retrieved from Pubmed, Embase, and Web of science, we identified 28 papers which adhered to strict inclusion and exclusion criteria. Evans blue (EB) leakage on the first day post-SCI was selected as the primary result. Secondary outcomes included the expression of tight junction (TJ) proteins and adhesion junction (AJ) proteins in protein immunoblotting. In addition, we measured functional recovery using the Basso, Beattie, Besnahan (BBB) score and we analyzed the relevant mechanisms to explore the similarities between different studies. Result: The forest plot of Evans blue leakage (EB leakage) reduction rate: the pooled effect size of the 28 studies was 0.54, 95% CI: 0.47–0.61, p < 0.01. This indicates that measures to mitigate BSCB damage significantly improved in reducing overall EB leakage. In addition TJ proteins (Occludin, Claudin-5, and ZO-1), AJ proteins (P120 and β-catenin) were significantly upregulated after treatment in all publications. Moreover, BBB scores were significantly improved. Comprehensive studies have shown that in t-SCI, inhibition of matrix metalloproteinases (MMPs) is the most commonly used mechanism to mitigate BSCB damage, followed by endoplasmic reticulum (ER) stress and the Akt pathway. In addition, we found that bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos), which inhibit the TIMP2/MMP signaling pathway, may be the most effective way to alleviate BSCB injury. Conclusion: This study systematically analyzes the experimental treatments and their mechanisms for reducing BSCB injury in the early stage of t-SCI. BMSC-Exos, which inhibit MMP expression, are currently the most effective therapeutic modality for alleviating BSCB damage. In addition, the regulation of MMPs in particular as well as the Akt pathway and the ER stress pathway play important roles in alleviating BSCB injury. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022324794.

Dataset Information

Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy.

Publications

Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy.

Similar Datasets

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