Hypoxia-stimulated mesenchymal stem cell-derived exosomes loaded by adhesive hydrogel for effective angiogenic treatment of spinal cord injury

Due to the limited efficacy of current clinical treatment strategies, functional recovery after traumatic spinal cord injury (SCI) remains a knotty problem to be solved. Apart from anti-inflammation and cell replenishing treatments, accumulating evidence implies that promoting angiogenesis would also potentially benefit tissue regeneration after SCI. In this research, inspired by the role of exosomes in cell-cell communication and exosomal alteration resulting from cells under stress, exosomes were engineered through hypoxia stimulation to mesenchymal stem cells and were proposed as an alternative for promoting angiogenesis in SCI therapy. Hypoxia-stimulated exosomes (hypo-Exo) were transplanted into the injured spinal cord via encapsulation in a peptide-modified adhesive hydrogel for pro-angiogenic therapy of SCI. The adhesive peptide PPFLMLLKGSTR-modified hyaluronic acid hydrogel replenished the spinal cavity caused by SCI and achieved the local delivery of exosomes. The hypoxia-inducible factor 1-alpha content in hypo-Exo was significantly increased, resulting in the overexpression of vascular endothelial growth factor in the endothelial cells surrounding the transplant system. Ultimately, prominent angiogenesis and functional recovery after injury were demonstrated both in vitro and in vivo , indicating the immense potential of hydrogel-encapsulated hypo-Exo in treating central nervous system trauma and other ischemia diseases. Implantation of hypoxia-stimulated mesenchymal stem cell-derived exosome encapsulated in an adhesive hydrogel induced pro-angiogenic spinal cord repair through transporting HIF-1α and upregulating vascular endothelial growth factor expression in recipient endothelial cells.