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Autophagy Induction by Neural Stem Cell-derived Extracellular Vesicles Aids Recovery from Spinal Cord Injury

Review of “Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy” from Cell Death and Disease by Stuart P. Atkinson

The transplantation of stem cells may promote functional recovery after acute spinal cord injury, partly through their neuroprotective capabilities; however, cells generally suffer from low survival rates in the inhospitable microenvironment of the injury, while the potential for surviving cell de-differentiation, immune rejection, and tumor formation represent additional obstacles. Treatment with neural stem cell-derived extracellular vesicles represents a potentially efficient solution to this problem, given their demonstrated potential as a treatment modality in neurodegenerative diseases thanks to their anti-inflammatory, neurogenic, and neurotrophic effects [1-3]. 

With this in mind, researchers led by Weihua Cai (First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China) recently assessed neural stem cell-extracellular vesicle therapy in a rat spinal cord injury model [4]. Excitingly, the authors discovered that their extracellular vesicle-based approach afforded a reduction in neuronal apoptosis and neuroinflammation and an increase in functional recovery at early stages thanks to the induction of autophagy, a regulated cellular mechanism that disassembles unnecessary or dysfunctional components.

Rong et al. began their study by in vitro by demonstrating that neural stem cell-extracellular vesicle treatment prevented glutamate-induced primary spinal neuron death. Mechanistically, extracellular vesicles activated autophagy, as evidenced by increased numbers of autophagosomes and increased expression of the autophagy-related proteins LC3BII and Beclin-1, which then prevented apoptosis and the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Importantly, the addition of an autophagy inhibitor prevented neural stem cell-extracellular vesicles from attenuating apoptosis and inflammation.

The authors then moved in vivo and tested neural stem cell-extracellular vesicle therapy in a rat spinal cord injury model, where they observed improved functional recovery and reduced lesion volume. Detailed analyses highlighted that extracellular vesicle treatment attenuated neuronal cell death, suppressed microglial activation, and reduced neuroinflammation; however, immunofluorescence and protein expression analyses also highlighted the induced expression of LC3BII and Beclin-1, suggesting that autophagy also contributed significantly to recovery from spinal cord injury in vivo. 

The authors hope that the discovery that neural stem cell-extracellular vesicles can suppress apoptosis and inflammatory processes by promoting autophagy will foster the development of new and efficient therapies for spinal cord injury, which still suffers from poor prognosis despite decades of basic and clinical research.

For more on neural stem cells, extracellular vesicles, and new approaches to spinal cord injury treatment, stay tuned to the Stem Cells Portal!

References

  1. Schindowski K, Belarbi K, and Buée L, Neurotrophic factors in Alzheimer’s disease: role of axonal transport. Genes, Brain and Behavior 2008;7:43-56.
  2. Stevanato L, Thanabalasundaram L, Vysokov N, et al., Investigation of Content, Stoichiometry and Transfer of miRNA from Human Neural Stem Cell Line Derived Exosomes. PLOS ONE 2016;11:e0146353.
  3. Webb RL, Kaiser EE, Scoville SL, et al., Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model. Translational Stroke Research 2018;9:530-539.
  4. Rong Y, Liu W, Wang J, et al., Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death & Disease 2019;10:340.