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MSCs-derived exosomes containing miR-486-5p attenuate cerebral ischemia and reperfusion (I/R) injury
Genbao Zhu1, La Jiang1, Kemeng Tan1
1General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou 234000, China.
Objectives:
This study aims to investigate the impact of mesenchymal stem cell (MSC)-derived exosomes (Exo) on cerebral ischemia and reperfusion (I/R) injury, along with the underlying mechanism.
Methods:
An animal model of cerebral ischemia was induced using middle cerebral artery occlusion (MCAO), and a cell model utilizing Neuro-2a cells was established through oxygen-glucose deprivation/reoxygenation (OGD/R). Exosomes isolated from mouse MSCs were administered to mice or used to stimulate Neuro-2a cells. Exosomes from MSCs transfected with miR-NC, miR-486-5p mimics, miR-486-5p inhibitor, or phosphatase and tensin homolog (PTEN) short hairpin RNAs (sh-PTEN) were employed to stimulate Neuro-2a cells. The regulatory axis of miR-486-5p and PTEN was confirmed through rescue experiments.
Results:
Exo-miR-486-5p mimics alleviated cerebral I/R injury, improving neurological deficits and reducing the infarct ratio. Furthermore, Exo-miR-486-5p mimics attenuated OGD/R-induced defects in cell viability and inhibited apoptosis in Neuro-2a cells. These mimics also reduced levels of lactate dehydrogenase (LDH) and malondialdehyde (MDA) while enhancing superoxide dismutase (SOD) activity, both in brain tissue homogenates of mice and cell supernatants. Mechanistically, PTEN was identified as a target of miR-486-5p, and the downregulation of PTEN notably elevated Exo-miR-486-inhibitor-induced reductions in cell viability while mitigating cell apoptosis.
Conclusion:
The results of this study demonstrate the potential of exosomes derived from MSCs to protect against cerebral I/R injury via the miR-486-5p and PTEN axis.
Insights
Mesenchymal stem cell exosomes carrying miR-486-5p protect the brain from ischemia and reperfusion injury by targeting PTEN. This discovery offers a novel therapeutic strategy for stroke treatment.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Molecular Biology
Background:
- Cerebral ischemia and reperfusion (I/R) injury remains a significant cause of neurological disability.
- Mesenchymal stem cells (MSCs) show therapeutic potential, with their exosomes (Exo) mediating many effects.
- Understanding the molecular mechanisms of MSC-derived exosomes in I/R injury is crucial for therapeutic development.
Purpose of the Study:
- To investigate the protective effects of MSC-derived exosomes on cerebral I/R injury.
- To elucidate the underlying molecular mechanism involving microRNA-486-5p (miR-486-5p) and phosphatase and tensin homolog (PTEN).
Main Methods:
- Cerebral I/R injury was modeled using middle cerebral artery occlusion (MCAO) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in Neuro-2a cells.
- Exosomes isolated from MSCs, engineered with miR-486-5p mimics or inhibitors, were administered or applied.
- The interaction between miR-486-5p and PTEN was confirmed via rescue experiments.
Main Results:
- MSC-derived exosomes with miR-486-5p mimics significantly reduced cerebral I/R injury, improved neurological function, and decreased infarct size.
- These exosomes enhanced cell viability, inhibited apoptosis, and modulated oxidative stress markers (LDH, MDA, SOD) in both animal and cell models.
- PTEN was identified as a direct target of miR-486-5p, and its downregulation mediated the protective effects of the exosomes.
Conclusions:
- MSC-derived exosomes exert neuroprotective effects against cerebral I/R injury.
- The miR-486-5p/PTEN axis is a key mechanism underlying the therapeutic benefits of these exosomes.
- This pathway represents a promising target for treating stroke and related neurological conditions.
