Human umbilical cord mesenchymal stem cells achieve neuroprotection via exosome-mediated anti-inflammation and blood-brain barrier recovery

Background Ischemia-reperfusion can aggravate cerebral damage. Mesenchymal stem cells have gained attention to improve the outcome of ischemia-reperfusion injury. This study aims to investigate the effects and mechanisms of human umbilical cord mesenchymal stem cells (hUC-MSCs) on cerebral ischemia-reperfusion injury in rats. Methods A middle cerebral artery occlusion-reperfusion (MCAO/R) model was successfully established, and hUC-MSCs or hUC-MSC-derived exosomes (hUC-MSC-exos) were injected into rats via stereotactic brain injection or the tail vein. Neurological functions were evaluated using Garcia, foot-fault, adhesive removal, and forepaw grip strength tests. In addition, we detected the expression of IL-1β, IL-10 and MMP9 in brain tissue using enzyme-linked immunosorbent assay. Immunofluorescence experiments detected the express of CD68 in the M1- microglia, the express of CD206 in the M2-microglia and the expression of Nrf2 in brain tissue. Western blotting experiments detected the expression of occludin, ZO-1, HO-1, and Nrf2 in brain tissue. Results HUC-MSCs significantly reduced the error rate and time to sense in the foot-fault test and in adhesive removal test. Similarly, hUC-MSCs can also significantly reduced infarct size and brain water content. HUC-MSCs improved morphology of brain tissue and cellular structure, including an increase in number of neurons containing Nissl bodies. And T2-weighted imaging revealed a reduction in high signal areas within the ischemic hemisphere in the cell group (hUC-MSCs). Further findings demonstrated that hUC-MSC-exos also improved neurological function and ameliorated the brain injury and morphological changes. In addition, hUC-MSC-exos decreased the contents of IL-1β, MMP-9, and the expression of CD68 (M1-microglia) r, augmented the expression of IL-10, ZO-1, Occludin, Nrf2, HO-1, and the expression of CD206 (M2-microglia). Conclusion These results indicated that human umbilical cord mesenchymal stem cells may excert neuroprotective effects in cerebral ischemia-reperfusion injury by inhibiting inflammation and protecting blood-brain barrier integrity via exosome-mediated Nrf2/HO-1 signaling pathway.