心脏干细胞CD9/Rac-1信号和SDF-1/CXCR4信号之间的协同作用及其对细胞迁移的影响

Cardiac Stem Cells (CSCs) are present in adult human and rodent hearts. The CSCs we are studying are Lin- c-kit+ stem cells and mainly located in atria. The CSCs are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. Following myocardial infarction, the CSCs promote cardiac repair by forming new blood vessels and myocytes. However, it remains unknown how the CSCs migrate from the atria into the left ventricle to repair the infarcted myocardium. Recently, results from our laboratory have shown that SDF-1/CXCR4 signaling mediated CSC migration post myocardial infarction, and which was regulated by SCF/c-kit signaling. Recently,the role of transmembrane proteins on CSC migration was further investigated, and surprisingly,the result showed that a tetraspan transmembrane protein (CD9) regulated CXCR4-mediated CSC migration, blockade of CD9 inhibited SDF-1/CXCR4-mediated CSC migration and Rac-1 activity as well. We therefore hypothesized that both CD9/Rac-1 and SDF-1/CXCR4 signaling pathways are present in CSCs, and interactions between these two signals may regulate CSC migration after myocardial infarction. Finally, the results from this study may help to design new strategies in the repair of infarcted myocardium by mobilizing the CSCs from atria to the ventricles.

在正常成年人和鼠心脏内含有心脏干细胞（CSC），主要分布在心房和房室交界处，心肌梗死(MI)后CSC能重建梗死的心肌组织。然而，CSC在常见的左心室发生MI后如何被激活并迁移入梗死灶的周围？我们的研究揭示，MI后SDF-1/CXCR4信号轴介导了CSC的迁移，且这一信号轴也受到其它信号（如SCF/c-kit）的调控。最近，我们观察了其他跨膜蛋白对CSC迁移的影响，发现四跨膜超蛋白CD9对CXCR4介导的CSC迁移发挥了调控作用，阻断CD9明显地抑制了SDF-1/CXCR4介导的CSC迁移，预实验显示阻断CD9后，Rac-1信号同时明显受到抑制，提示可能建立了CD9/Rac-1信号。我们推测：CD9/Rac-1信号可能通过与SDF-1/CXCR4进行信号交流，从而对CSC迁移发挥调控作用。其研究结果将进一步阐明MI后CSC迁移的机制，为最终形成一个“动员”CSC修复MI的治疗策略。

在正常成年人和鼠心脏内含有c-kit+干细胞，主要分布在心房和房室交界处，心肌梗死(MI)后c-kit+干细胞能重建梗死的心肌组织并改善心功能。然而，c-kit+干细胞在常见的左心室发生MI后如何被激活并迁移入梗死灶的周围尚不完全清楚。本项目在以前的研究基础上，就这一问题继续展开了有关的研究，希望能进一步阐明其机制。本项目的研究揭示，心肌梗死后在心肌组织中的c-kit+干细胞中，建立了SDF-1/CXCR4信号轴，调控了c-kit+干细胞的迁移；同时，该信号轴在c-kit+干细胞内还可调控CD9的表达从而影响RAC1活性，证实了SDF-1/CXCR4信号与CD9/RAC1信号之间存在相互作用，并共同调控c-kit+干细胞的骨架重排，从而促进细胞的迁移。这为心肌梗死后动员c-kit+干细胞修复梗死的心肌组织之治疗策略，提供新的理论基础和实验依据。该项目进展顺利，实验研究均已完成，部分结果在进行分析和总结，并撰写论文。该项目已发表SCI论文5篇；期间培养博士研究生3名。