Sfrp2 and Cardiac Progenitor Cells in Regenerative Response to Ischemic Injury

一些研究表明，分泌型卷曲相关蛋白2 （Sfrp 2）是Wnt通路抑制剂，是心肌损伤修复的关键介质 并且已经显示出抑制肌细胞凋亡，诱导血管生成， 抑制纤维化。在几个模型系统中，Sfrp 2是分化的调节剂，但 尚未进行直接阐述Sfpr 2在以下疾病中的意义的研究： 心肌细胞更新及Sfpr 2在心肌祖细胞中的作用 活化、增殖和分化仍有待阐明。的 对CPC扩张和分化的监管是一个基本但尚不明确的问题， 心血管生物学和再生医学方面。我们的初步 体外和体内的研究表明，CPC对Wnt/Sfrp 2有反应， 信号我们的数据表明，Sfrp 2抑制典型的Wnt 3a信号传导， 增强成人c-Kit+/Sca 1 + CPC的分化。因此，Sfrp 2在 Sfpr 2/Wnt相互作用对成年心肌细胞更新的调控 提出了一个有趣的问题为了解决这个问题，我们假设Sfrp 2，通过 调节Wnt经典途径，是心脏祖细胞的关键调节因子， 增殖和谱系特化。为了验证这一假设，使用培养的 CPC，我们将在体外研究Sfpr 2和Wnt 3a对CPC的重要性， 增殖和分化，并阐明Wnt/β-连环蛋白的作用， 经典信号通路在体内，我们将通过评估来扩展这些研究。 Sfrp 2在心肌细胞更新中的作用 内源性CPC命运。我们将使用遗传命运绘图研究和血统 跟踪方案，以检查内源性 心脏干细胞，这些细胞分化为心脏运动细胞， 确定Sfrp 2在这些过程中的作用，我们将询问 Wnt/β-连环蛋白经典信号通路在介导 Sfrp 2在体内对CPC的作用。在完成这项研究计划后，我们将 已经描述了Sfrp 2信号在成体心脏干细胞中的作用 提供了关于调节这些细胞的途径的新见解， 关于它们的离体或体内调节以用于治疗的新机会 目的

Several studies have suggested that Secreted Frizzled-related protein 2 (Sfrp2), a Wnt pathway inhibitor, is a key mediator of myocardial wound repair and has been shown to inhibit myocyte apoptosis, induce angiogenesis and inhibit fibrosis. In several model systems, Sfrp2 is a regulator of differentiation yet no studies have been performed that directly address the significance of Sfpr2 in cardiomyocyte renewal and the role of Sfpr2 in cardiac progenitor cell (CPC) activation, proliferation and differentiation remains to be elucidated. The regulation of CPC expansion and differentiation is a fundamental but yet unclear aspect of cardiovascular biology and regenerative medicine. Our preliminary studies, both in vitro and in vivo, suggest CPCs are responsive to Wnt/Sfrp2 signaling. Our data suggest that Sfrp2 inhibits canonical Wnt3a signaling and enhances differentiation in adult c-Kit+/Sca1+ CPCs. Thus, the role of the Sfrp2 in modulation of adult cardiomyocyte renewal by a potential Sfpr2/Wnt interaction poses an intriguing question. To address this, we hypothesize that Sfrp2, by modulating Wnt canonical pathway, is a key regulator of cardiac progenitor proliferation and lineage specification. To test this hypothesis, using cultured CPCs, we will investigate in vitro the importance of Sfpr2 and Wnt3a on CPC proliferation and differentiation, and elucidate the role of the Wnt/b-catenin canonical signaling pathway. In vivo, we will extend these studies by evaluating the role of Sfrp2 on cardiomyocyte renewal by examining its effects on endogenous CPC fate. We will use a genetic fate-mapping study and lineage tracing protocols to examine the proliferation and activation of endogenous cardiac stem cells, the differentiation of these cells to cardiac mocytes and determine the role of Sfrp2 on these processes and we will enquire about the importance of the Wnt/b-catenin canonical signaling pathway in mediating the Sfrp2 effects on CPCs in vivo. At the conclusion of this research proposal we will have characterized the role of Sfrp2 signaling in adult cardiac stem cells providing novel insights about the pathways that regulate these cells and opening new opportunities about their modulation ex vivo or in vivo for therapeutic purposes.