Sphingosine 1-phosphate elicits RhoA-dependent proliferation and MRTF-A mediated gene induction in CPCs.
Sphingosine 1-phosphate elicits RhoA-dependent proliferation and MRTF-A mediated gene induction in CPCs.
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DOI：
10.1016/j.cellsig.2016.04.006
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发表时间：
2016-08
影响因子：
4.8
通讯作者：
Purcell NH
中科院分区：
文献类型：
--
作者：
Castaldi A;Chesini GP;Taylor AE;Sussman MA;Brown JH;Purcell NH
尽管c-kit+心脏祖细胞（CPCs）目前已用于临床试验，但我们对其增殖和分化的分子机制的理解仍存在相当大的差距。在哺乳动物细胞类型中，g蛋白偶联受体（GPCR）在调节这些过程中发挥重要作用，因此我们评估了从成年小鼠心脏分离的c-kit+细胞中GPCR mRNA的表达。我们的数据首次全面概述了这类心脏受体在心肌细胞中的分布，并揭示了与成人心肌细胞的显著区别。我们重点研究了与RhoA激活偶联的gpcr，特别是鞘氨醇-1 -磷酸（S1P）的gpcr。S1P2和S1P3受体是小鼠和人心肌细胞中最丰富的S1P1受体亚型，而心肌细胞主要表达S1P1受体。与凝血酶和血清一样，用S1P治疗CPCs，通过RhoA信号通路增加增殖，当Rho被C3毒素抑制时，其显著衰减证明了这一点。进一步的分析表明，S1P和血清诱导的增殖都是通过S1P2和S1P3受体亚型来调节的，这些受体亚型与g - α12/13偶联，引发RhoA活化。转录共激活因子MRTF-A被S1P激活，通过其核积累和RhoA/MRTF-A荧光素酶报告基因的诱导来评估。此外，S1P处理通过激活MRTF-A增加心脏谱系标记物Mef2C和GATA4以及平滑肌标记物GATA6的表达。总之，我们在CPCs中描述了一个s1p调控的信号通路，该通路引入了靶向S1P2/3受体、Gα12/13或RhoA的可能性，以影响c-kit+ CPCs的增殖和承诺，并改善损伤后心肌的反应。
Although c-kit+ cardiac progenitor cells (CPCs) are currently used in clinical trials there remain considerable gaps in our understanding of the molecular mechanisms underlying their proliferation and differentiation. G-protein coupled receptors (GPCRs) play an important role in regulating these processes in mammalian cell types thus we assessed GPCR mRNA expression in c-kit+ cells isolated from adult mouse hearts. Our data provide the first comprehensive overview of the distribution of this fundamental class of cardiac receptors in CPCs and reveals notable distinctions from that of adult cardiomyocytes. We focused on GPCRs that couple to RhoA activation in particular those for sphingosine-1 -phosphate (S1P). The S1P2 and S1P3 receptors are the most abundant S1P receptor subtypes in mouse and human CPCs while cardiomyocytes express predominantly S1P1 receptors. Treatment of CPCs with S1P, as with thrombin and serum, increased proliferation through a pathway requiring RhoA signaling, as evidenced by significant attenuation when Rho was inhibited by treatment with C3 toxin. Further analysis demonstrated that both S1P- and serum- induced proliferation are regulated through the S1P2 and S1P3 receptor subtypes which couple to Gα12/13 to elicit RhoA activation. The transcriptional co-activator MRTF-A was activated by S1P as assessed by its nuclear accumulation and induction of a RhoA/MRTF-A luciferase reporter. In addition S1P treatment increased expression of cardiac lineage markers Mef2C and GATA4 and the smooth muscle marker GATA6 through activation of MRTF-A. In conclusion, we delineate an S1P–regulated signaling pathway in CPCs that introduces the possibility of targeting S1P2/3 receptors, Gα12/13 or RhoA to influence the proliferation and commitment of c-kit+ CPCs and improve the response of the myocardium following injury.
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影响因子：
8
作者：
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通讯作者：
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影响因子：
2.7
作者：
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作者：
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作者：
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