Signals Through Glycoprotein 130 Regulate the Endothelial Differentiation of Cardiac Stem Cells
Signals Through Glycoprotein 130 Regulate the Endothelial Differentiation of Cardiac Stem Cells
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DOI：
10.1161/atvbaha.108.174870
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发表时间：
2009-05
期刊：
影响因子：
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通讯作者：
T. Mohri;Y. Fujio;Masanori Obana;T. Iwakura;Koichi Matsuda;Makiko Maeda;J. Azuma
中科院分区：
文献类型：
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作者：
T. Mohri;Y. Fujio;Masanori Obana;T. Iwakura;Koichi Matsuda;Makiko Maeda;J. Azuma
心脏Sca-1+细胞最初被鉴定为多能干细胞。为了解决其分化的调节，我们研究了促炎细胞因子对其内皮分化的影响。方法和结果-我们检测了促炎细胞因子包括肿瘤坏死因子-（TNF-）、白细胞介素（IL）-1、IL-6、IL-11和心肌营养素-1（CT-1）对心脏Sca-1+细胞分化的影响。通过RT-PCR和免疫细胞化学分析，IL-11和CT-1的受体系统使用糖蛋白130（gp 130），诱导Sca-1+细胞中的内皮特异性基因，但不诱导TNF-、IL-1或IL-6。免疫印迹分析显示IL-11和CT-1激活gp 130下游靶点信号转导子和转录激活子3（STAT 3），但不激活其他细胞因子。尽管IL-6受体在Sca-1+细胞中不是内源性表达的，但IL-6在可溶性IL-6受体（一种与STAT 3磷酸化相关的激动性受体）存在下表现出诱导内皮标志物的活性。此外，通过其显性负性形式或siRNA抑制STAT 3，抑制了IL-11和CT-1对内皮特异性基因的诱导。最后，LIF和IL-11转录上调梗死后心肌，伴随着Sca-1+/VE-钙粘蛋白+细胞的诱导。结论Gp 130/STAT 3信号通路在心脏Sca-1+细胞内皮分化的调控中起重要作用。
Objective—Cardiac Sca-1+ cells were originally identified as multipotent stem cells. To address the regulation of their differentiation, we investigated the effects of the proinflammatory cytokines on their endothelial differentiation. Methods and Results—We examined the effects of the proinflammatory cytokines including tumor necrosis factor- (TNF-), interleukin (IL)-1, IL-6, IL-11, and cardiotrophin-1 (CT-1) on the cardiac Sca-1+ cell differentiation. IL-11 and CT-1, whose receptor systems use glycoprotein 130 (gp130), induced endothelial-specific genes in Sca-1+ cells, but not TNF-, IL-1, or IL-6, analyzed by RT-PCR and by immunocytochemistry. Immnunoblot analyses showed that IL-11 and CT-1 activated signal transducer and activator of transcription 3 (STAT3), a downstream target of gp130, but not other cytokines. Though IL-6 receptor is not endogenously expressed in Sca-1+ cells, IL-6 exhibited the activity to induce the endothelial markers in the presence of soluble IL-6 receptor, an agonistic receptor, associated with STAT3 phosphorylation. Moreover, the inhibition of STAT3, by its dominant-negative form or siRNA, suppressed the induction of endothelial specific genes by IL-11 and CT-1. Finally, LIF and IL-11 transcripts were upregulated in postinfarct myocardium, accompanied by the induction of Sca-1+/VE-cadherin+ cells. Conclusions—Gp130/STAT3 pathway plays critical roles in the regulation of endothelial differentiation of cardiac Sca-1+ cells.