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BMSC-derived exosomal piR-161382 alleviates spinal cord ischemia/reperfusion injury by targeting MCU to inhibit
Xiangyi Tong1, Qing Ma2, Guihang An3
1Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, China.
Background:
Pyroptosis, NLRC4 and mitochondrial calcium uniporter (MCU)'s role in spinal cord ischemia/reperfusion injury (SCIRI) remain unclear. The role of exosomal piRNAs in SCIRI is underexplored. We aimed to investigate the neuroprotective effects of exosomes obtained from bone marrow mesenchymal stem cells (BMSCs) overexpressing piR-161382 in SCIRI.
Methods:
We studied MCU and NLRC4 expression changes after SCIRI and OGD/R in rats. piR-161382 and piR-161382's interaction with MCU was validated. Exosome were analyzed via TEM and NTA, and confirmed by Western blotting, and DiI-labeled exosomes tracked in vivo. Hindlimb recovery was assessed with Tarlov scores. Effects of NLRC4/MCU inhibition, piR-161382 overexpression, and BMSC-derived exosomal piR-161382 on pyroptosis markers were evaluated. Cell viability, ROS, mitochondrial membrane potential, and BSCB permeability were measured.
Results:
MCU and NLRC4 levels expressed in spinal neurons. NLRC4 knockout improved cell viability and reduced pyroptosis markers after OGD/R. Inhibiting MCU or using mito-tempo decreased ROS, increased mitochondrial membrane potential (MMP), and alleviated NLRC4-mediated pyroptosis, while MCU overexpression reversed these effects. PiR-161382's interaction with MCU was confirmed. piR-161382 mimic treatment reduced ROS, improved MMP, and suppressed NLRC4 activation and pyroptosis after OGD/R, with reversal upon MCU agonist SPER. BMSC-derived exosomal piR-161382 reduced MCU, ROS, and pyroptosis markers, enhancing cell survival. In SCIRI rats treated with piR-161382-overexpressing exosomes, hindlimb function improved, MCU, NLRC4, and pyroptosis proteins decreased, and blood-spinal cord barrier integrity was restored.
Conclusions:
BMSC-derived exosomes overexpressing piR-161382 mitigate SCIRI by targeting MCU, reducing ROS, and inhibiting NLRC4-mediated neuronal pyroptosis.
Insights
Bone marrow mesenchymal stem cell-derived exosomes engineered with piR-161382 show neuroprotective effects against spinal cord injury. These exosomes target mitochondrial calcium uniporter (MCU) to reduce oxidative stress and inhibit pyroptosis, improving functional recovery.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Spinal cord ischemia/reperfusion injury (SCIRI) involves pyroptosis, NLRC4, and mitochondrial calcium uniporter (MCU), but their roles are unclear.
- The therapeutic potential of exosomal piRNAs in SCIRI remains largely unexplored.
- This study investigates the neuroprotective effects of exosomes from bone marrow mesenchymal stem cells (BMSCs) engineered to overexpress piR-161382 in SCIRI.
Purpose of the Study:
- To elucidate the roles of MCU and NLRC4 in SCIRI.
- To investigate the interaction between piR-161382 and MCU.
- To evaluate the therapeutic efficacy of BMSC-derived exosomes overexpressing piR-161382 in mitigating SCIRI.
Main Methods:
- Assessed MCU and NLRC4 expression in rat models of SCIRI and oxygen-glucose deprivation/reperfusion (OGD/R).
- Validated piR-161382's interaction with MCU using molecular techniques.
- Characterized exosomes and tracked their in vivo distribution; evaluated functional recovery using Tarlov scores.
Main Results:
- NLRC4 knockout and MCU inhibition reduced OGD/R-induced pyroptosis, cell death, and reactive oxygen species (ROS), while increasing mitochondrial membrane potential (MMP).
- piR-161382 mimic treatment suppressed NLRC4-mediated pyroptosis and ROS, with effects modulated by MCU activity.
- BMSC-derived exosomes overexpressing piR-161382 improved hindlimb function in SCIRI rats, reduced MCU and NLRC4 levels, inhibited pyroptosis, and restored blood-spinal cord barrier integrity.
Conclusions:
- BMSC-derived exosomes overexpressing piR-161382 exert neuroprotection in SCIRI.
- The mechanism involves targeting MCU, reducing ROS, and inhibiting NLRC4-mediated neuronal pyroptosis.
- This approach offers a promising therapeutic strategy for spinal cord injury.
