SDF-1/CXCR4和SDF-1/CXCR7双信号的相互作用及其对心脏干细胞迁移的影响

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 myocardial infarction increases SCF/c-kit signaling and consequently upregulates CXCR4 expression, which promotes CSC migration via SDF-1/CXCR4 signaling. However, blockade of SCF/c-kit signaling can not completely inhibit CXCR4 expression and CXCR4-dependent migration of CSCs, suggesting that additional signaling pathways are involved. More recently, CXCR7, a new receptor for SDF-1, has been discovered, our preliminary data showed that myocardial infarction increaes CXCR7 expression in CSCs, and blocking CXCR7 significantly inhibits CXCR4-dependent migration of CSCs, indicating both CXCR4 and CXCR7 are involved in the SCF-1-induced migration of CSCs after myocardial infarction. We therefore hypothesized that both SDF-1/CXCR4 and SDF-1/CXCR7 signaling pathways are present in CSCs, and interactions between SDF-1/CXCR4 and SDF-1/CXCR7 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SCF/c-kit信号介导了CSC表达CXCR4，从而构建了SDF-1/CXCR4信号并介导了CSC的迁移；但阻断SCF信号并未完全阻断CXCR4的表达及其介导的CSC迁移，提示有其它信号的介入。CXCR7是最近发现的CXCR4"同胞"受体，预实验显示MI后CSC也表达了CXCR7，阻断CXCR7能明显阻断CXCR4所介导的CSC迁移，提示MI后CSC表达了CXCR4和CXCR7，两受体均参与了CSC的迁移。我们推测：MI后CSC内构建了SDF-1/CXCR4和SDF-1/CXCR7双信号系统，两信号可能相互作用并共同介导CSC的迁移。其研究结果将进一步阐明MI后CSC迁移的机制。

主要存在于心房和房室交界处的心脏干细胞（CSC），在常见的左心室发生心肌梗死（MI）后如何被激活并迁移入梗死灶的周围？本课题组一直围绕着这一问题展开研究，希望能明了其机制。本项目的研究显示，心肌梗死后CSC表达了SDF-1的两个“同胞”受体，CXCR4和CXCR7，同时心肌组织表达了SDF-1，从而构成了SDF-1/CXCR4和SDF-1/CXCR7双信号系统，两信号系统分别介导了CSC的迁移；进一步的研究发现，SDF-1/CXCR4和SDF-1/CXCR7双信号系统通过AKT和ERK之间发生了相互作用，进而调控了CSC的迁移，从而影响了心肌梗死后的修复及其心功能的改善。其结果进一步探讨了心室心肌梗死后，位于心房和房室交界处的心脏干细胞向心肌梗死灶迁移的机制，为运用“动员”心脏干细胞来修复梗死的心肌之治疗策略的形成提供了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6篇，全国大会发言2人次，尚有部分资料在总结中；期间培养博士研究生6名。