Neural stem cell-derived exosomes facilitate spinal cord functional recovery after injury by promoting angiogenesis

Abstract

Acute traumatic spinal cord injury is a devastating event without effective therapeutic approach. The feeble plasticity of spinal cord microvascular endothelial cells (SCMECs) after trauma is one of the major causes for the exacerbation of spinal cord injury. Therefore, improving the plasticity and regeneration of SCMECs is crucial to promote recovery after spinal cord injury. For the present study, we explored the influence of exosomes derived from neural stem cells (NSCs-Exos) on the spinal cord microvascular regeneration after spinal cord injury and determined the underlying mechanisms. After the primary NSCs and SCMECs were extracted, exosomes were isolated from NSCs conditioned medium and used to co-incubated with the SCMECs in vitro, and then the effect of exosomes on the angiogenic activities of SCMECs was measured. The candidate molecules involved in the NSCs-Exos-mediated angiogenesis were screened using Western blotting. The effect of NSCs-Exos on angiogenesis and spinal cord functional recovery after injury in vivo was analyzed. The results demonstrated that NSCs-Exos could enhance the angiogenic activities of SCMECs, and were highly enriched in VEGF-A. The level of VEGF-A was downregulated in NSCsshVEGF-A-Exos and the pro-angiogenic effects on cocultured SCMECs were inhibited. Furthermore, NSCs-Exos significantly accelerated the microvascular regeneration, reduced the spinal cord cavity, and improved the Basso mouse scale scores in spinal cord injury mice. This work provides the evidence of the underlying mechanism of NSCs-Exos-mediated angiogenesis and suggests a novel therapeutic target for spinal cord injury. Impact statement The feeble plasticity of SCMECs after trauma is one of the major causes for the exacerbation of SCI. Therefore, improving the regeneration ability of SCMECs is crucial to promote spinal cord functional recovery after injury. Our current study uncovered that NSCs-Exos could promote SCMECs migration, tube formation and proliferation in vitro, and further identified that exosomal VEGF-A mediated the pro-angiogenic effect. Furthermore, we observed a remarkable microvascular density increase, spinal cord cavity shrinkage, and motor function recovery in SCI mice treated with NSCs-Exos, which confirmed the therapeutic effects of NSCs-Exos to alleviate SCI. Downregulating VEGF-A partially abolished these effects of NSCs-Exos. This is the first study to reveal that NSCs-Exos has the pro-angiogenic effect on SCMECs by transferring VEGF-A and promote microvascular regeneration and tissue healing, indicating that NSCs-Exos can become a promising therapeutic bioagent for facilitating the functional recovery of SCI.

Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis

“…Animal experiment procedures were conducted according to the Guideline of Animal Care and Use Committee of Central South University (permit number: 20170101). Mice received spinal contusion trauma as previously described [ 12 ]. Briefly, after each mouse was fully anesthetized with 1 mg kg −1 of ketamine intramuscularly and 1.5–2.5% isoflurane, a vertebral laminectomy at thoracic T9–10 was performed to expose the spinal cord.…”

Extracellular Vesicles as Innovative Tool for Diagnosis, Regeneration and Protection against Neurological Damage

“…MSC-derived EVs have been found to promote spinal cord injury repair in animal models through different processes. Exosomal delivery to the spinal cord, locally or systemically, induces axonal growth [ 198 , 199 ], counteracts neuroinflammation [ 200 , 201 , 202 ], reduces glial scar formation [ 203 ], downregulates harmful astroglial properties [ 204 , 205 ], attenuates neuronal apoptosis [ 206 ], promotes angiogenesis [ 200 , 207 ] and protects the blood–spinal cord barrier [ 208 ]. Intranasal administration of MSC-derived exosomes containing small interfering RNA (siRNA) for PTEN have been successfully used to stimulate spinal cord injury repair by downregulating PTEN [ 209 ].…”

Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis

“…Animal experiment procedures were conducted according to the Guideline of Animal Care and Use Committee of Central South University (Permit numbers: 20170101). Mice received spinal contusion trauma as previously described [12]. Brie y, after each mouse was fully anaesthetized with 1 mg kg −1 of ketamine intramuscularly and 1.5-2.5% iso urane, a vertebral laminectomy at thoracic T9-10 was performed to expose the spinal cord.…”