hUCMSC-derived Exosomes promote spinal cord repair by alleviating the disruption of the blood-spinal cord barrier

Abstract After spinal cord injury (SCI), the integrity of the blood–spinal cord barrier (BSCB) is closely related to the occurrence of secondary injury and functional recovery. Previous studies have shown that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos) promote nerve repair in multiple degenerative neurological diseases. However, it remains largely elusive whether hUCMSC-exos can promote spinal cord repair after SCI. In this study, hUCMSC-exos were injected through the tail vein immediately after the successful establishment of SCI in a rat model. We showed that the loss of neurons and the destruction of pathological structures were significantly reduced after hUCMSC-exos treatment, and the motor function of rats was also greatly improved. Mechanistically, hUCMSC-exos promote spinal cord repair by affecting autophagy and BSCB integrity. In vitro, the expression of BSCB-associated proteins in human brain microvascular endothelial cells (HBMECs) was significantly reduced in the OGD model, and this reduction was significantly mitigated by treatment with hUCMSC-exos. In addition, autophagic flux was significantly activated after OGD, and hUCMSC-exos treatment further activated autophagic flux. When this process was inhibited by 3-MA (an autophagy inhibitor), the protective effect of hUCMSC-exos was significantly reversed both in vivo and in vitro. These findings suggest that hUCMSC-exos reduce the permeability of the BSCB and promote functional recovery after SCI by activating autophagic flux in endothelial cells. Our study is the first to demonstrate the protective effect of hUCMSC-exos on the BSCB and the underlying mechanism, shedding light on the potential therapeutic benefit for SCI.