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目的：探究不同时间点移植后骨髓间充质干细胞（BMSCs）的选择性迁移对大鼠全脑缺血/再灌注模型认知功能的影响以及可能的分子机制。方法：成年雄性SD 大鼠80 只，随机分为四组，全脑缺血再灌注组（model 组，n=20），假手术组（sham组，n=20），造模1 d后较早BMSCs 移植组（early组，n=20），造模7 d后较晚移植组（late 组，n=20）。结扎双侧颈总动脉并结合低血压建立大鼠全脑缺血/再灌注模型，后于不同时间点尾静脉移植GFP+BMSCs。造模后1、3、7、14 d用酶联免疫法（ELISA）检测模型损伤区域大鼠皮层和海马部位的SDF-1α和MCP-1的表达水平，28 d后进行Morris水迷宫检测认知改变，32 d 通过免疫组织化学染色和Western blot 观察GFP+BMSCs 的分布情况。结果：水迷宫实验表明细胞移植组相比sham组参数有显著提升，且early 组相比 late组表现更好（P<0.05）；GFP免疫组化和western 结果表明，early组BMSCs移植后分布于海马更多（P<0.05），而late 组中BMSCs 在皮层分布更多（P<0.05）；ELISA 结果表明，造模后1 d模型大鼠海马区域的SDF-1α和MCP-1 的表达水平呈现短暂的相对性上调（P <0.05），而造模7 d 后相关皮层区域的SDF-1琢表达缓慢上调（P<0.05）。结论：造模后早期（1 d）移植BMSCs 比晚期能更好的改善模型大鼠的认知功能；造模后SDF-1α和MCP-1 的时空变化可能介导了BMSCs的选择行迁移，后者直接决定了对模型大鼠的认知功能改善的疗效。

英文摘要:

Objective:To investigate the effect of bone marrow mesenchymal stem cells (BMSCs) transplantation at different time points on the learning and memory ability in the rat model of transient global cerebral ischemia and explore the possible molecular mechanism of it.Methods:80 adult male SD rats were randomly divided into model group (n=20), sham group (n=20), early group (n=20) and late group (n=20). The surgery of bilateral common carotid artery occlusion and hypoperfusion was performed to establish the rat model of transient global cerebral ischemia, after which BMSCs transplantation were performed at 1d (early) and 7d (late) via tail vein injection. ELISA test were used to detect the hippocampal and cortical variation of SDF-1αand MCP-1 at 1, 3, 7 and 14 d after the model establishment. Morris Water Maze tests were performed to investigate the cognitive changes of the four groups at 28 d, and then immunohistochemistry and Western blot tests of GFP were used to detect the differential migration of BMSCs.Results:Cell transplantation groups showed improved cognitive ability and the early group turned out to be better than the late one (P<0.05). Immunohistochemistry and Western blot tests showed that cell grafts in the early group tend to migrate to the hippocampus (P<0.05), while the ones in the late group tend to migrate to the cortex (P<0.05); ELISA test showed that the expression levels of SDF-1α and MCP-1 were relatively up-regulated at 1 d (P<0.05), while the expression of SDF-1αwas slowly up-regulated after 7 d (P<0.05).Conclusion:Early BMSCs transplantation is more effective than later ones in terms of cognitive improvement in the rat model of transient global cerebral ischemia. The differential migration of transplanted BMSCs may be mediated by temporal and spatial changes of SDF-1αand MCP-1, and finally determines the cognitive outcomes.

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