心脏干细胞CXCL14/CXCR4新型信号轴的建立及其对细胞迁移的调控

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 SDF-1/CXCR4 signaling which promotes CSC migration. However, blockade of SDF-1 signaling can not completely inhibit CXCR4-dependent migration of CSCs, suggesting that additional signaling pathways are involved. More recently, CXCL14 has been discovered to bind with CXCR4, our preliminary data showed that myocardial infarction increaes CXCL14 expression in injuried myocardium, and blocking CXCL14 significantly inhibits CXCR4-dependent migration of CSCs, indicating there may be a new CXCL14/CXCR4 signal axis in CSCs,which is involved in the migration of CSCs after myocardial infarction. We therefore hypothesized that myocardial infarction may lead to an increase in CXCL14 expression, which binds to CXCR4 on the surface of CSCs, and the CXCL14/CXCR4 signaling 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；但阻断SDF-1并未完全阻断CXCR4介导的CSC迁移，提示有其它信号的介入。CXCL14最近被发现能与CXCR4高度结合，预实验显示MI后心肌组织表达了CXCL14，阻断CXCL14能明显阻断CXCR4所介导的CSC迁移，提示CSC可能建立了CXCL14/CXCR4信号轴并介导了CSC迁移。我们推测：MI后心肌组织表达的CXCL14与CSC CXCR4结合，在CSC内建立了CXCL14/CXCR4新型信号系统并介导了CSC迁移。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的治疗策略提供理论依据。

既往研究表明c-kit+干细胞有助于心肌梗死（MI）后心功能的改善，但c-kit+干细胞迁移至梗死灶周围的具体机制仍有待阐明。我们以往的研究发现，SDF-1/CXCR4信号轴是介导c-kit+干细胞迁移的重要途径，而阻断SDF-1未能完全阻断CXCR4介导的迁移，提示还有其它信号的参与。CXCL14是CXC趋化因子家族中的一员，与SDF-1具有高度相似的结构，参与调控多种细胞的增殖和迁移，但其在心肌梗死中的作用尚不清楚。本研究通过构建小鼠MI模型，证实MI后梗死周围心肌组织中CXCL14的表达明显升高。体外实验表明，CXCL14通过激活AKT、ERK1/2及NF-κB信号通路诱导c-kit+干细胞的增殖与迁移。尽管CXCL14仍未发现明确的受体，但已有研究证实，CXCL14以高亲和力并且特异性结合于CXCR4。在本研究中用CXCL14刺激c-kit+干细胞10min后，可以观察到CXCR4的磷酸化水平明显升高。通过siRNA沉默c-kit+干细胞中CXCR4表达后，CXCL14诱导的c-kit+干细胞迁移数量明显下降，并且显著抑制CXCL14诱导激活的AKT、ERK1/2及NF-κB通路。以上研究结果表明，MI后梗死周围心肌组织表达的CXCL14通过与c-kit+干细胞表面的CXCR4结合，形成CXCL14/CXCR4信号轴，通过激活AKT、ERK1/2及NF-κB信号通路参与调控c-kit+干细胞的迁移和增殖。这为c-kit+干细胞的迁移提供了新的分子机制，并为CXCL14成为促进c-kit+干细胞迁移的潜在靶点提供理论依据，从而为动员c-kit+干细胞修复MI提供新的思路。

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