Kim Gyu-Hee, Subash Marasini, Yoon Jeong Seon, Jo Darong, Han Jihun, Hong Ji Man, Kim Sung-Soo, Suh-Kim Haeyoung
Department of Anatomy, Ajou University School of Medicine, Suwon, Korea.
Department of Biomedical Sciences, Ajou Graduate School, Suwon, Korea.
Int J Stem Cells. 2020 Mar 30;13(1):127-141. doi: 10.15283/ijsc19111.
Stem cell therapy is a promising strategy for treating neurological diseases but its effectiveness is influenced by the route of administration and the characteristics of the stem cells. We determined whether neural induction of mesenchymal stem cells (MSCs) was beneficial when the cells were delivered intra-arterially through the carotid artery.
MSCs were neurally induced using a retroviral vector expressing the neurogenic transcription factor neurogenin-1 (Ngn1). The LacZ gene encoding bacterial β-galactosidase was used as a control. Ischemic stroke was induced by transluminal occlusion of the middle cerebral artery and 3 days later the MSCs were delivered intra-arterially through the internal carotid artery. Magnetic resonance imaging analysis indicated that compared to MSCs expressing LacZ (MSCs/LacZ), MSCs expressing Ngn1 (MSCs/Ngn1) exhibited increased recruitment to the ischemic region and populated this area for a longer duration. Immunohistochemical analysis indicated that compared to MSCs/LacZ, MSCs/Ngn1 more effectively alleviated neurological dysfunction by blocking secondary damage associated with neuronal cell death and brain inflammation. Microarray and real-time PCR analysis indicated that MSCs/Ngn1 exhibited increased expression of chemotactic cytokine receptors, adherence to endothelial cells, and migration ability.
Neural induction with Ngn1 increases the homing ability of MSCs, enhancing their engraftment efficiency in the ischemic rat brain. Intra-arterial delivery of neurally induced MSCs/Ngn1 3 days after ischemic injury blocks neuronal cell death and inflammation, and improves functional recovery. Thus, intra-arterial administration of stem cells with neural properties may be a novel therapy for the treatment of ischemic stroke.
干细胞疗法是治疗神经疾病的一种有前景的策略，但其有效性受给药途径和干细胞特性的影响。我们确定了间充质干细胞（MSC）经颈动脉动脉内注射时，对其进行神经诱导是否有益。
使用表达神经源性转录因子神经生成素-1（Ngn1）的逆转录病毒载体对MSC进行神经诱导。编码细菌β-半乳糖苷酶的LacZ基因用作对照。通过大脑中动脉腔内闭塞诱导缺血性卒中，3天后经颈内动脉将MSC动脉内注射。磁共振成像分析表明，与表达LacZ的MSC（MSC/LacZ）相比，表达Ngn1的MSC（MSC/Ngn1）向缺血区域的募集增加，且在该区域驻留的时间更长。免疫组织化学分析表明，与MSC/LacZ相比，MSC/Ngn1通过阻断与神经元细胞死亡和脑炎症相关的继发性损伤，更有效地减轻了神经功能障碍。基因芯片和实时PCR分析表明，MSC/Ngn1趋化细胞因子受体的表达增加、对内皮细胞的黏附以及迁移能力增强。
用Ngn1进行神经诱导可提高MSC的归巢能力，增强其在缺血大鼠脑中的植入效率。缺血性损伤3天后动脉内注射经神经诱导的MSC/Ngn1可阻断神经元细胞死亡和炎症，并改善功能恢复。因此，动脉内注射具有神经特性的干细胞可能是治疗缺血性卒中的一种新疗法。
