Stem cell factor/c-kit signaling mediated cardiac stem cell migration via activation of p38 MAPK
Stem cell factor/c-kit signaling mediated cardiac stem cell migration via activation of p38 MAPK
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DOI：
10.1007/s00395-007-0690-z
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发表时间：
2008-05-01
影响因子：
9.5
通讯作者：
Wang, Guoping
中科院分区：
文献类型：
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作者：
Kuang, Dong;Zhao, Xia;Wang, Guoping
目的研究发现大鼠心脏中存在心脏干细胞(CSCs)，它们能重建携带血液的新血管和心肌细胞所形成的分化良好的心肌。然而，心肌梗死(MI)后CSCs是如何迁移到梗死灶周围的呢？CSC迁移过程中的信号转导机制尚不清楚。方法与结果采用左冠状动脉结扎诱导大鼠心肌梗死模型。免疫组织化学染色和Western blotting分析SCF蛋白表达，RT-PCR检测SCF mRNA表达。从大鼠心脏中分离心脏干细胞，并使用48孔趋化小室系统进行心脏干细胞迁移试验。大鼠心肌梗死后第5天，梗死灶周围干细胞因子(SCF)基因和蛋白表达显著增加，与此相匹配的是CSCs在梗死灶周围积聚增多，心功能改善，p38 MAPK选择性抑制剂SB203580可阻断此作用。在体外实验中，SCF以浓度依赖的方式诱导CSC迁移，抗SCF受体抗体(c-kit)可阻断SCF诱导的CSC迁移。Western印迹分析显示，SCF诱导的CSCs中磷酸化的p38MAPK(磷酸化p38MAPK)显著增加，抑制p38MAPK活性可显著减弱SCF诱导的CSCs迁移。结论SCF/c-kit信号通路可能通过激活p38MAPK介导CSCs的迁移。
Objective It was reported that there are cardiac stem cells (CSCs) in the rat heart, and they could reconstitute well-differentiated myocardium that are formed by blood-carrying new vessels and myocytes. However, how do the CSCs migrate into the peri-infarcted areas after myocardial infarction (MI)? It remains entirely unknown about the signal transduction involved in the migration of CSCs.Methods and results Rat heart MI was induced by left coronary artery ligation. Both immunohistochemical staining and Western blotting analysis was performed to detect the expression of SCF protein, and RT-PCR was conducted for the expression of SCF mRNA. Cardiac stem cells were isolated from rat hearts, and a cardiac stem cell migration assay was performed using a 48-well chemotaxis chamber system. On day 5 after MI in rats, the expression of stem cell factor (SCF) mRNA and protein was significantly increased in the peri-infarcted area, which was matched with more accumulation of CSCs in the region and improvement of cardiac function, which was blocked by p38 MAPK selective inhibitor SB203580. In in vitro experiments, SCF induced CSC migration in a concentration-dependent manner, and the antibody against SCF receptor (c-kit) blocked the SCF-induced CSC migration. Western blot analysis showed that the phosphorylated p38 MAPK (Phospho-p38 MAPK) was highly increased in the SCF-treated CSCs, and the inhibition of p38 MAPK activity significantly attenuated SCF-induced the migration of CSCs.Conclusion It demonstrated that SCF/c-kit signaling may mediate the migration of CSCs via activation of p38 MAPK.