Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Int Immunopharmacol. 2021 Jan;90:107207. doi: 10.1016/j.intimp.2020.107207. Epub 2020 Dec 4.
Experimental autoimmune encephalomyelitis (EAE) is a mouse model for the human multiple sclerosis, which is characterized by inflammation in the central nervous system (CNS), de-myelination of axonal neurons, and loss of motor coordination. The aim of the current study was to evaluate the effect of intranasal administration of mesenchymal stem cells (MSCs) and small extracellular vesicle (SEV) derived from the MSC (MSC-SEV) on disease activity and antigen-specific responses in the EAE mouse model. MSCs (5 × 10) were administered intranasally to EAE mice (n = 5) on the 15th and 24th days after immunization. In addition, the intranasal administration of MSC-SEV (10 μg) was used to treat EAE mice (n = 5) on a daily basis from the 15th to the 27th day after induction of the disease. The outcomes of therapies were evaluated using studying clinical symptoms and histological analysis of CNS lesions. Moreover, T cell proliferation, the frequency of regulatory T cells, the expression of transcription factors of T-helper subsets, and the levels of their corresponded cytokines were evaluated in splenocytes culture that was stimulated with specific-antigen. The results of treatment of EAE mice with MSC- SEV and MSC showed a significant decrease in the clinical scores, and it was found that treatment with MSC-SEV was more effective in alleviating clinical scores than MSC. In addition, the decrease in clinical symptoms was associated with an increase in immunomodulatory responses, including an increase in the frequency of Foxp3+ CD25+ regulatory T cells. Moreover, the level of TGF-β was increased by both treatments; however, interleukin-10 was increased only by MSC treatment. Ultimately, it was achieved that the intranasal administration of MSC-SEV to EAE mice was more effective than the administration of MSC to reduce clinical scores and histological lesions of the CNS tissue.
实验性自身免疫性脑脊髓炎 (EAE) 是人类多发性硬化症的小鼠模型，其特征为中枢神经系统 (CNS) 炎症、轴突神经元脱髓鞘和运动协调丧失。本研究旨在评估鼻内给予间充质干细胞 (MSCs) 和源自 MSC 的小细胞外囊泡 (MSC-SEV) 对 EAE 小鼠模型疾病活动和抗原特异性反应的影响。在免疫后第 15 天和第 24 天，将 5×10 的 MSCs 鼻内给予 EAE 小鼠 (n=5)。此外，从疾病诱导后的第 15 天到第 27 天，每天鼻内给予 MSC-SEV (10μg) 治疗 EAE 小鼠 (n=5)。通过研究中枢神经系统病变的临床症状和组织学分析来评估治疗效果。此外，通过用特异性抗原刺激脾细胞培养物来评估 T 细胞增殖、调节性 T 细胞的频率、T 辅助亚群转录因子的表达及其对应的细胞因子水平。用 MSC-SEV 和 MSC 治疗 EAE 小鼠的结果表明临床评分明显降低，并且发现 MSC-SEV 治疗在缓解临床评分方面比 MSC 更有效。此外，临床症状的减轻与免疫调节反应的增加有关，包括 Foxp3+CD25+调节性 T 细胞的频率增加。此外，两种治疗方法均可增加 TGF-β水平，而只有 MSC 治疗可增加白细胞介素-10 水平。最终，发现与 MSC 相比，鼻内给予 MSC-SEV 对 EAE 小鼠更有效，可降低临床评分和 CNS 组织的组织学病变。
