Hypoxia-treated umbilical mesenchymal stem cell alleviates spinal cord ischemia-reperfusion injury in SCI by circular RNA circOXNAD1/miR-29a-3p/FOXO3a axis

Spinal cord ischemia reperfusion (SCIR) injury leads to spinal cord function injury, neural dysfunction and sometimes paralysis or even paraplegia, which severely impair the physical and mental health of individuals. Mesenchymal stem cells (MSCs) are a group of stem cells that have been widely studied for treatment of various diseases. This work aimed to study the therapeutic potential of hypoxia-induced exosomal circular RNA OXNAD1 from human umbilical cord mesenchymal stem cells (HucMSCs) against SCIR. We established an in vivo rat spinal cord injury (SCI) model and conducted treatment with exosomes that isolated from hypoxia-HucMSCs. Hypoxia-HucMSCs-derived exosomal circOXNAD1 alleviated the spinal cord tissue injury in SCI, improved limb motor function, decreased production of inflammatory factors including the IL-1 beta, IL-6, and TNF-alpha. The in vitro hypoxia and reoxygenation (H/R) model demonstrated that Hypoxia-HucMSCs-derived exosomal circOXNAD1 improved neuron proliferation and alleviated apoptosis. Mechanistically, circOXNAD1 directly interact with miR-29a-3p and miR-29a-3p targets the 3 ' UTR of FOXO3a in neurons. Inhibition of miR-29a-3p and overexpression of FOXO3a reversed the effects of circOXNAD1 depletion in PC12 cell phenotypes. In conclusion, Hypoxia elevated the level circOXNAD1 in exosomes that derived from HuMSCs. The exosomal circOXNAD1 alleviated SCI through sponging miR-29a-3p and consequently elevated the FOXO3a expression. Our findings provided novel evidence for MSC-derived exosomal circOXNAD1in the treatment of SCI.