Abstract
Mesenchymal stem cell (MSC) transplantation has been shown to represent a potential treatment for traumatic spinal cord injury (SCI). However, there are several obstacles that need to be overcome before MSCs can be considered for clinical application, such as failure of MSCs to reach the spinal cord lesion core and possible tumor formation. Recent studies have suggested that MSC treatment is beneficial owing to paracrine-secreted factors. Extracellular vesicles are considered to be some of the most valuable paracrine molecules. However, the therapeutic mechanism of extracellular vesicles on spinal cord injury has not been studied clearly. Therefore, our study investigated the effect of systemic administration of extracellular vesicles on the loss of motor function after SCI and examined the potential mechanisms underlying their effects. Disruption of the blood-spinal cord barrier (BSCB) is a crucial factor that can be detrimental to motor function recovery. Pericytes are an important component of the neurovascular unit, and play a pivotal role in maintaining the structural integrity of the BSCB. Our study demonstrated that administration of bone mesenchymal stem cell-derived extracellular vesicles (BMSC-EV) reduced brain cell death, enhanced neuronal survival and regeneration, and improved motor function compared with the administration of BMSC-EV free culture media (EV-free CM). Besides, the BSCB was attenuated and pericyte coverage was significantly decreased in vivo. Furthermore, we found that exosomes reduced pericyte migration via downregulation of NF-κB p65 signaling, with a consequent decrease in the permeability of the BSCB. In summary, we identified that extracellular vesicles treatment suppressed the migration of pericytes and further improved the integrity of the BSCB via NF-κB p65 signaling in pericytes. Our data suggest that extracellular vesicles may serve as a promising treatment strategy for SCI.
Highlights
Traumatic spinal cord injury (SCI) causes permanent motor/sensory dysfunction, and even paralysis and death, resulting in a considerable reduction in the quality of life of the patient (Eckert and Martin, 2017)
Unique exosome markers, including CD63, CD9, and CD81 were confirmed by western blot analysis, while exosome-specific proteins were not detected in EV-free CM
At 1 dpi, a dramatic reduction in the number of TUNEL-positive cells was found in the bone mesenchymal stem cell-derived extracellular vesicles (BMSC-EV) group compared with the SCI+phosphate buffered saline (PBS) group and EV-free CM treated group (Figures 2A,D)
Summary
Traumatic spinal cord injury (SCI) causes permanent motor/sensory dysfunction, and even paralysis and death, resulting in a considerable reduction in the quality of life of the patient (Eckert and Martin, 2017). Considerable research has been carried out on the mechanisms involved, there are still no effective treatments for SCI. Recent research has suggested that MSCs may play a therapeutic role via the release of paracrine factors and stimulation of host cells, instead of through their differentiation (Caplan and Dennis, 2006; Caplan and Correa, 2011). Several studies have demonstrated that EV participate in therapeutic effects, such as wound regeneration and reduction of neuronal cell death following cerebral ischemia (Goodarzi et al, 2018; Zagrean et al, 2018). It is unclear how EV promote motor recovery post-SCI. To get a better understanding of the potential mechanisms involved in EV therapy, we further studied how EV protect the BSCB following SCI
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