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Updated: Jun 8, 2025
Synergetic Use of Neural Precursor Cells and Self-assembling Peptides in Experimental Cervical Spinal Cord Injury
Published on: February 23, 2015
Engineered melatonin-pretreated plasma exosomes repair traumatic spinal cord injury by regulating miR-138-5p/SOX4
Hao Chen1, Huihui Sun1, Yaqing Yang2
1Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University/Clinical Medical College, Yangzhou University, Yangzhou, China.
Background:
Neuroinflammation plays a crucial role in the repair of spinal cord injury (SCI), with microglia, pivotal in neuroinflammation, driving either degeneration or recovery in this pathological process. Recently, plasma-derived exosomes (denoted Exos) have presented a high capacity for promoting functional recovery of SCI through the anti-inflammatory effects, and pretreated exosomes are associated with better outcomes. Thus, we aimed to explore whether melatonin-pretreated plasma-derived exosomes (denoted MExo) could exert superior effects on SCI, and attempted to elucidate the potential mechanisms.
Methods:
Electron microscopy, nanoparticle tracking analysis, and western blot were applied to delineate the distinctions between Exos and MExos. To assess their therapeutic potentials, we established a contusion SCI rat model, complemented by a battery of in vitro experiments comparing both groups. Subsequently, a miRNA microarray analysis was conducted, followed by a series of rescue experiments to elucidate the specific role of miRNAs in MExos. To further delve into the molecular mechanisms involved, we employed western blot analysis and the luciferase reporter gene assay.
Results:
Melatonin promoted the release of exosome from plasma, concurrently amplifying their anti-inflammatory properties. Furthermore, it was discerned that MExos facilitated a transition in microglia polarization from M1 to M2 phenotype, a phenomenon more pronounced than that observed with Exos. In an endeavor to elucidate this variance, we scrutinized miRNAs exhibiting elevated expression levels in MExos, pinpointing miR-138-5p as a pivotal element in this dynamic. Following this, an in-depth investigation into the role of miR-138-5p was undertaken, which uncovered its efficacy in driving phenotypic alterations within microglia. The analysis of downstream genes targeted by miR-138-5p revealed that it exerted a negative regulatory influence on SOX4, which was found to obstruct the generation of M2-type microglia and the secretion of anti-inflammatory cytokines, thereby partially elucidating the mechanism behind miR-138-5p's regulation of microglia polarization.
Conclusions:
We innovatively observed that melatonin enhanced the anti-inflammatory function of Exos, which further decreased the expression of SOX4 by delivering miR-138-5p. This inhibition promoted the conversion of M1 microglia to M2 microglia, thus offering a viable option for the treatment of SCI.
The Translational Potential Of This Article:
This study highlights that melatonin enhances the anti-inflammatory function of Exos through delivery of miR-138-5p. Activation of miR-138-5p/SOX4 axis by engineered melatonin-pretreated plasma exosomes may be a potential target for SCI treatment.
Insights
Melatonin-pretreated exosomes (MExo) enhance spinal cord injury (SCI) repair by reducing inflammation. MExo deliver miR-138-5p, which suppresses SOX4, promoting beneficial M2 microglia polarization for SCI treatment.
Area of Science:
- Regenerative Medicine
- Neuroscience
- Biotechnology
Background:
- Neuroinflammation is critical in spinal cord injury (SCI) repair, with microglia mediating degeneration or recovery.
- Plasma-derived exosomes (Exos) show therapeutic potential for SCI via anti-inflammatory effects.
- Pretreated exosomes may offer improved outcomes for SCI treatment.
Purpose of the Study:
- To investigate if melatonin-pretreated plasma-derived exosomes (MExo) provide superior therapeutic effects on SCI compared to Exos.
- To elucidate the underlying molecular mechanisms of MExo's action in SCI.
Main Methods:
- Characterization of Exos and MExos using electron microscopy, nanoparticle tracking analysis, and western blot.
- Assessment of therapeutic potential in a rat SCI model and in vitro experiments.
- miRNA microarray analysis and rescue experiments to identify key miRNAs and their targets (e.g., SOX4) using western blot and luciferase assays.
Main Results:
- Melatonin enhanced exosome release and amplified their anti-inflammatory properties.
- MExos significantly promoted microglia polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype.
- miR-138-5p, upregulated in MExos, was identified as a key mediator, suppressing SOX4 expression and facilitating M2 microglia polarization.
Conclusions:
- Melatonin enhances exosome anti-inflammatory function by increasing miR-138-5p delivery, leading to SOX4 downregulation.
- This miR-138-5p/SOX4 axis modulation promotes M1 to M2 microglia conversion, offering a novel therapeutic strategy for SCI.
- Engineered MExos targeting the miR-138-5p/SOX4 pathway represent a promising therapeutic target for spinal cord injury.
