CXCL12/CXCR7/CXCR4轴对神经干细胞迁移的机制研究

CXCL12 is a key chemokine which is widely expressed in central nerves system.It is well known that CXCL12 induces neural progenitor cell migration through CXCR4.Recently,CXCR7 has been found as the sencond receptor for CXCL12, however, little is known if CXCR7 is involved in neural progenitor cell migration.Our in vitro expriments suggest that CXCR7 is important for neural progenitor cell migration.For further studies,we try to confirm the results in vivo using CXCR7- and CXCR4- knockout mice.And then our studies mainly focus on the mechanisms of CXCL12/CXCR7/CXCR4 axis in neural progenitor cell migration. We first use stripe assay to detect the CXCL12-induced neural progenitor cell migration and then detect the change of extracellular matrix by gene chip.We also use microfluidic chamber to monitor the dynamic change of Rac,Rab5 and Rab11 in neural progenitor cell migration by confocal microscope. Our research try to figure out the mechanisms of CXCL12-induced neural progenitor cell migration in details which is essencial for development of central nerves system.

CXCL12是一种重要的趋化因子，其在中枢神经系统中广泛表达。已有的文献表明CXCL12通过其CXCR4受体诱导神经干细胞的迁移，而近期发现CXCL12还有第二个受体CXCR7，其是否在神经干细胞迁移过程中发挥功能却没有报导。申请者前期的体外实验结果表明CXCR7也在神经干细胞迁移过程中发挥重要的作用。据此进一步在体内验证CXCR7基因敲除或者CXCR4基因敲除对神经干细胞迁移的影响,并对两种受体如何介导神经干细胞迁移的机制进行研究。通过条带迁移实验和全基因组表达谱芯片联用检测CXCL12引起的神经干细胞迁移过程中细胞外基质的变化以及通过微流小室和激光共聚焦技术实时探测神经干细胞迁移过程中Rac,Rab5,Rab11的变化情况并阐明这些蛋白与神经干细胞迁移的关系。本研究首次深入探讨了CXCL12/CXCR7/CXCR4轴在神经干细胞迁移的功能和机制，对神经干细胞治疗具有重要的理论指导意义。

神经干细胞的迁移在大脑发育,成年神经再生和大脑损伤的神经修复发挥了至关重要的功能。CXCL12和它的受体CXCR4调节了神经干细胞迁移,然而目前新发现了CXCR7是CXCL12的另一个受体，CXCR4或者CXCR7的拮抗剂都能阻断CXCL12介导的神经干细胞迁移。通过迁移小室和条带迁移实验进一步证实了CXCL12可以诱导CXCR4缺失神经干细胞的迁移，从而说明CXCR7可以单独介导迁移。在体移植CXCR4缺失神经干细胞迁移实验进一步证实了CXCR7的迁移作用，并且此作用可以被CXCR7特异性的拮抗剂阻断。接下去的分子机制研究表明CXCR7和Rac1在神经干细胞的极化端相互作用并激活ERK信号通路。这些结果揭示了CXCR7在CXCL12介导的神经干细胞迁移过程中的重要作用和机制，从而进一步深入了解了神经发生发育过程中的分子机制。