Wang Ye, Deng Yubin, Zhou Guang-Qian
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Er Lu, 510080, Guangzhou, PR China.
Brain Res. 2008 Feb 21;1195:104-12. doi: 10.1016/j.brainres.2007.11.068. Epub 2007 Dec 14.
Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) can promote functional recovery of brain after stroke with the mechanism regulating the BMSCs migration to ischemic penumbra poorly understood. Interaction between stromal cell-derived factor-1alpha (SDF-1alpha) and its cognate receptor CXCR4 is crucial for homing and migration of multiple stem cell types. Their potential role in mediating BMSC migration in ischemic brain has not been demonstrated. In this study, ischemic brain lesion model was created in rats by permanent middle cerebral artery occlusion and green fluorescent protein (GFP)-labeled BMSCs were intravenously injected. Immunohistochemical staining showed that BMSCs were able to enter the route from olfactory areas to cortex of the rat brain. Significant recovery of modified Neurological Severity Score was observed at days 14 and 28. Interestingly, the SDF-1alpha mRNA and protein were predominantly localized in the ischemic penumbral, peaked by 3-7 days and retained at least 14 days post-transplantation. On the other hand, the CXCR4 expression by BMSCs was elevated under hypoxia. The pre-treatment with the CXCR4-specific antagonist AMD3100 significantly prevented the migration of BMSCs to the injured brain. Taken together, these observations indicate that systemically administered BMSCs can migrate to the ischemic lesion of brain along with the olfactory-thalamus and hippocampus-cortex route. The interaction of locally produced SDF-1alpha and CXCR4 expressed on the BMSC surface plays an important role in the migration of transplanted cells, suggesting that it might be a potential approach to modulate the expression of the two molecules in order to further facilitate the therapeutic effects using BMSCs.
骨髓间充质干细胞（BMSCs）移植可促进中风后脑功能恢复，但其调节BMSCs向缺血半暗带迁移的机制尚不清楚。基质细胞衍生因子-1α（SDF-1α）与其同源受体CXCR4之间的相互作用对多种干细胞类型的归巢和迁移至关重要。它们在介导缺血性脑内BMSC迁移中的潜在作用尚未得到证实。在本研究中，通过永久性大脑中动脉闭塞在大鼠中建立缺血性脑损伤模型，并静脉注射绿色荧光蛋白（GFP）标记的BMSCs。免疫组织化学染色显示，BMSCs能够进入大鼠脑从嗅觉区域到皮质的路径。在第14天和第28天观察到改良神经功能缺损评分有显著恢复。有趣的是，SDF-1α mRNA和蛋白主要定位于缺血半暗带，在移植后3 - 7天达到峰值，并至少保留14天。另一方面，BMSCs在缺氧条件下CXCR4表达升高。用CXCR4特异性拮抗剂AMD3100预处理可显著阻止BMSCs向损伤脑的迁移。综上所述，这些观察结果表明，全身给药的BMSCs可沿嗅丘脑和海马 - 皮质路径迁移至脑缺血损伤部位。局部产生的SDF-1α与BMSC表面表达的CXCR4之间的相互作用在移植细胞的迁移中起重要作用，这表明调节这两种分子的表达可能是进一步促进使用BMSCs治疗效果的潜在方法。
