脊髓损伤（SCI）的病理学复杂性，包括轴突丢失，炎症，神经胶质瘢痕形成和血管破裂，提示单一疗法可能不足以治疗SCI。最近，有人建议hMSC治疗是治疗SCI的首选方法，因为hMSC可以分泌神经保护，血管生成和免疫调节的多因素治疗因子。然而，与全身给药相比，将hMSC直接植入受伤的脊髓具有明显的侵袭性，因此限制了临床治疗SCI的翻译。而且，植入的hMSC显示出较差的存活率，并且hMSC在分化的脊髓中不分化为神经元。这些问题表明，hMSC外泌体可能是治疗SCI的合适治疗剂。由于hMSC外泌体中存在多种治疗性生长因子及其mRNA，与衍生自其他细胞类型（如成纤维细胞）的外泌体相比，它们具有出色的组织修复能力。此外，最近的一些研究报道，hMSC外泌体也显示出对中枢神经系统（CNS）疾病的治疗作用（20） 包括SCI。尽管hMSC外泌体治疗优于hMSC治疗，但hMSC外泌体技术应进一步改进以用于临床应用。hMSC仅形成少量的外泌体（每天来自106个细胞的1-4μg外泌体蛋白）。因此，需要长期的细胞培养和大量的hMSC来产生足够量的hMSC外泌体用于临床应用。但是，晚期传代的MSC的生长因子基因和蛋白质表达明显降低，这将减少分泌性外泌体中治疗性生长因子及其mRNA的数量。因此，在这项研究中，使用了源自hMSC的外泌体模拟纳米囊泡来治疗SCI。
近日，首尔国立大学的In-Bo Han和Byung-Soo Kim团队报告了离子处理的hMSCs中制备了氧化铁纳米颗粒(IONP)结合外泌体模拟纳米囊泡(NV-IONP)，并在脊髓损伤的临床相关模型中评估其治疗效果。与由未经处理的hMSCs制备的外泌体模拟纳米囊泡(NV)相比，NV- ionp不仅含有可作为磁导导航工具的离子，而且还携带更多可被输送到靶细胞的治疗性生长因子。NV-IONP内治疗性生长因子数量的增加归因于离子缓慢电离为铁离子，铁离子激活hMSCs中JNK和c-Jun信号级联。体内在磁引导下全身注射NV-IONP可显著增加损伤脊髓内NV-IONP的累积量。累积的NV-IONP增强了损伤脊髓的血管形成，减轻了炎症和细胞凋亡，从而改善了脊髓功能。综上所述，这些发现突出了治疗效果增强的细胞外纳米囊泡的发展，并证明了它们修复损伤脊髓的可行性。
The complexity of pathology in spinal cord injury (SCI), including axonal loss, inflammation, glial scar formation, and blood vessel disruption, suggests that mono-therapy may be inadequate for the treatment of SCI. Recently, hMSC therapy has been suggested as a favored approach for the treatment of SCI, as hMSCs can secrete multifactorial therapeutic factors for neuroprotection, angiogenesis, and immunomodulation. However, the direct implantation of hMSCs to an injured spinal cord is significantly invasive as compared to systemic administration, and thus it limits clinical translation for the treatment of SCI. Moreover, implanted hMSCs show poor survival rate, and hMSCs do not differentiate into neurons in injured spinal cord. These issues suggest that hMSC-exosomes may be an adequate therapeutic agent for the treatment of SCI. As various therapeutic growth factors and their mRNAs are present in hMSC-exosomes, they have an outstanding ability to repair tissue as compared to exosomes derived from other cell types such as fibroblasts. Additionally, several recent studies reported that hMSC-exosomes also show therapeutic effects for central nervous system (CNS) diseases including SCI. Although hMSC-exosome therapy has advantages over hMSC therapy, hMSC-exosome technology should be further improved for clinical application. hMSCs form only a small amount of exosomes (1–4 µg exosome proteins from 106 cells per day). Therefore, longterm cell culture and large number of hMSCs are required to produce sufficient amount of hMSC-exosomes for clinical applications. However, the MSCs at the late passage exhibit significantly reduced gene and protein expression of growth factors, which would reduce the quantity of therapeutic growth factors and their mRNAs in the secreted exosomes. Therefore in this study, they utilized exosome-mimetic nanovesicles derived from hMSCs for treatment of SCI.
Recently, Professor In-Bo Han and Professor Byung-Soo Kim from Seoul National University fabricated iron oxide nanoparticle (IONP)–incorporated exosome-mimetic nanovesicles (NV-IONP) from IONP-treated hMSCs, and evaluated their therapeutic efficacy in a clinically relevant model for spinal cord injury. Compared to exosome-mimetic nanovesicles (NV) prepared from untreated hMSCs, NV-IONP not only contained IONPs which act as a magnet-guided navigation tool but also carried greater amounts of therapeutic growth factors that can be delivered to the target cells. The increased amounts of therapeutic growth factors inside NV-IONP were attributed to IONPs that are slowly ionized to iron ions which activate the JNK and c-Jun signaling cascades in hMSCs. In vivo systemic injection of NV-IONP with magnetic guidance significantly increased the amount of NV-IONP accumulating in the injured spinal cord. Accumulated NV-IONP enhanced blood vessel formation, attenuated inflammation and apoptosis in the injured spinal cord, and consequently improved spinal cord function. Taken together, these findings highlight the development of therapeutic efficacy-potentiated extracellular nanovesicles and demonstrate their feasibility for repairing injured spinal cord.
DOI:10.1021/acs.nanolett.8b01816
吴硕