MicroRNA-421-3p-abundant small extracellular vesicles derived from M2 bone marrow-derived macrophages attenuate apoptosis and promote motor function recovery via inhibition of mTOR in spinal cord injury

Abstract

Background Spinal cord injury (SCI) has a very disabling central nervous system impact but currently lacks effective treatment. Bone marrow-derived macrophages (BMDMs) are recruited to the injured area after SCI and participate in the regulation of functional recovery with microglia. Previous studies have shown that M2 microglia-derived small extracellular vesicles (SEVs) have neuroprotective effects, but the effects of M2 BMDM-derived sEVs (M2 BMDM-sEVs) have not been reported in SCI treatment. Results In this study, we investigated the role of M2 BMDM-sEVs in vivo and in vitro for SCI treatment and its mechanism. Our results indicated that M2 BMDM-sEVs promoted functional recovery after SCI and reduced neuronal apoptosis in mice. In addition, M2 BMDM-sEVs targeted mammalian target of rapamycin (mTOR) to enhance the autophagy level of neurons and reduce apoptosis. MicroRNA-421-3P (miR-421-3p) can bind to the 3′ untranslated region (3′UTR) of mTOR. MiR-421-3p mimics significantly reduced the activity of luciferase-mTOR 3′UTR constructs and increased autophagy. At the same time, tail vein injection of inhibitors of SEVs (Inh-sEVs), which were prepared by treatment with an miR-421-3p inhibitor, showed diminished protective autophagy of neuronal cells in vivo. Conclusions In conclusion, M2 BMDM-sEVs inhibited the mTOR autophagy pathway by transmitting miR-421-3p, which reduced neuronal apoptosis and promoted functional recovery after SCI, suggesting that M2 BMDM-sEVs may be a potential therapy for SCI.

Exosomes derived from miR-26a-modified MSCs promote axonal regeneration via the PTEN/AKT/mTOR pathway following spinal cord injury

“…Bioinformatics analysis and data mining revealed that miR-26a is differentially expressed after SCI. In this research, we verified that exosomes transplantation could improve functional recovery in a SCI rat model, which is consistent with some previous studies [ 65 , 66 ]. Hematoxylin and eosin staining, assessment with the BBB scale, DTI, and MEP recording revealed more significant improvements in the miR-26a-overexpressing exosome group than the other groups.…”

Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury

“…The primary bone marrow-derived macrophages (BMDMs) were obtained and cultured as previously reported [ 21 ]. The femur and tibia of 4-week-old mice were removed, from which bone marrow was flushed out with cold PBS.…”

“…Recent evidence demonstrated that macrophages-derived exosomes promote axonal degeneration by delivering functional NADPH oxidase 2 complexes to injured axons [ 20 ]. Moreover, small extracellular vesicles derived from M2 bone marrow could attenuate apoptosis and promote motor function recovery following SCI [ 21 ]. However, it remains unclear whether M1 macrophages-derived exosomes regulate BSCB integrity, and the underlying mechanisms still need further investigation.…”

Fosl1 Targets AMPK to Inhibit Autophagy-Mediated Anti-Apoptotic and Anti-Inflammatory Effects in Spinal Cord Injury

“…Innovations in stem cell transplantation once presented an effective strategy to provide extrinsic nerve cells to build new networks and rescue neurological function, but satisfactory outcomes have yet to be been achieved [50]. The SCI secondary injury plays a more important role in the neuronal loss, which is often accompanied by in ammation, apoptosis, autophagy, and necrosis [51,52]. However, the precise mechanism is still unclear.…”