Sun Jinmei, Wei Zheng Zachory, Gu Xiaohuan, Zhang James Ya, Zhang Yongbo, Li Jimei, Wei Ling
Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Exp Neurol. 2015 Oct;272:78-87. doi: 10.1016/j.expneurol.2015.03.011. Epub 2015 Mar 20.
Intracerebral hemorrhagic stroke (ICH) causes high mortality and morbidity with very limited treatment options. Cell-based therapy has emerged as a novel approach to replace damaged brain tissues and promote regenerative processes. In this study we tested the hypothesis that intranasally delivered hypoxia-preconditioned BMSCs could reach the brain, promote tissue repair and improve functional recovery after ICH. Hemorrhagic stroke was induced in adult C57/B6 mice by injection of collagenase IV into the striatum. Animals were randomly divided into three groups: sham group, intranasal BMSC treatment group, and vehicle treatment group. BMSCs were pre-treated with hypoxic preconditioning (HP) and pre-labeled with Hoechst before transplantation. Behavior tests, including the mNSS score, rotarod test, adhesive removal test, and locomotor function evaluation were performed at varying days, up to 21days, after ICH to evaluate the therapeutic effects of BMSC transplantation. Western blots and immunohistochemistry were performed to analyze the neurotrophic effects. Intranasally delivered HP-BMSCs were identified in peri-injury regions. NeuN+/BrdU+ co-labeled cells were markedly increased around the hematoma region, and growth factors, including BDNF, GDNF, and VEGF were significantly upregulated in the ICH brain after BMSC treatment. The BMSC treatment group showed significant improvement in behavioral performance compared with the vehicle group. Our data also showed that intranasally delivered HP-BMSCs migrated to peri-injury regions and provided growth factors to increase neurogenesis after ICH. We conclude that intranasal administration of BMSC is an effective treatment for ICH, and that it enhanced neuroregenerative effects and promoted neurological functional recovery after ICH. Overall, the investigation supports the potential therapeutic strategy for BMSC transplantation therapy against hemorrhagic stroke.
脑内出血性中风（ICH）导致的死亡率和发病率很高，而治疗选择非常有限。基于细胞的疗法已成为一种替代受损脑组织并促进再生过程的新方法。在本研究中，我们测试了以下假设：经鼻递送的缺氧预处理骨髓间充质干细胞（BMSCs）可以到达大脑，促进组织修复并改善脑出血后的功能恢复。通过向成年C57/B6小鼠纹状体内注射IV型胶原酶诱导出血性中风。动物被随机分为三组：假手术组、经鼻BMSC治疗组和载体治疗组。BMSCs在移植前进行缺氧预处理（HP）并用Hoechst预先标记。在脑出血后的不同天数（最长21天）进行行为测试，包括改良神经功能缺损评分（mNSS）、转棒试验、黏附去除试验和运动功能评估，以评估BMSC移植的治疗效果。进行蛋白质免疫印迹和免疫组织化学分析神经营养作用。在损伤周围区域鉴定出经鼻递送的HP-BMSCs。在血肿区域周围，神经元核抗原（NeuN）+/5-溴脱氧尿嘧啶核苷（BrdU）+双标记细胞明显增加，并且在BMSC治疗后的脑出血大脑中，包括脑源性神经营养因子（BDNF）、胶质细胞源性神经营养因子（GDNF）和血管内皮生长因子（VEGF）在内的生长因子显著上调。与载体组相比，BMSC治疗组的行为表现有显著改善。我们的数据还表明，经鼻递送的HP-BMSCs迁移到损伤周围区域，并提供生长因子以增加脑出血后的神经发生。我们得出结论，经鼻给予BMSC是治疗ICH的有效方法，并且它增强了神经再生作用并促进了脑出血后的神经功能恢复。总体而言，该研究支持BMSC移植治疗出血性中风的潜在治疗策略。
