Sfrp2 and Cardiac Progenitor Cells in Regenerative Response to Ischemic Injury

描述（由申请人提供）：多项研究表明，Wnt通路抑制剂Sfrp2 （Secreted frizzledrelated protein 2）是心肌损伤修复的关键介质，并已被证明可抑制心肌细胞凋亡、诱导血管生成和抑制纤维化。在一些模型系统中，Sfpr2是一种分化调节剂，但没有研究直接解决Sfpr2在心肌细胞更新中的意义，Sfpr2在心脏祖细胞（CPC）激活、增殖和分化中的作用仍有待阐明。CPC扩张和分化的调控是心血管生物学和再生医学的一个基本但尚不清楚的方面。我们在体外和体内的初步研究表明，cpc对Wnt/ strp2信号通路有反应。我们的数据表明，Sfrp2抑制典型Wnt3a信号传导并增强成人c-Kit+/Sca1+ cpc的分化。因此，通过潜在的Sfpr2/Wnt相互作用，sfp2在调节成人心肌细胞更新中的作用提出了一个有趣的问题。为了解决这个问题，我们假设Sfrp2通过调节Wnt规范通路，是心脏祖细胞增殖和谱系规范的关键调节剂。为了验证这一假设，我们将利用体外培养的CPC，研究Sfpr2和Wnt3a对CPC增殖和分化的重要性，并阐明Wnt/b-catenin典型信号通路的作用。在体内，我们将通过检测其对内源性CPC命运的影响来评估srp2在心肌细胞更新中的作用，从而扩展这些研究。我们将使用遗传命运定位研究和谱系追踪方案来检查内源性心脏干细胞的增殖和激活，这些细胞向心脏细胞的分化，并确定Sfrp2在这些过程中的作用，我们将探讨Wnt/b-catenin经典信号通路在介导体内Sfrp2对心肌细胞的影响中的重要性。在这项研究计划的结论中，我们将描述Sfrp2信号在成人心脏干细胞中的作用，为调节这些细胞的途径提供新的见解，并为其体外或体内调节治疗目的开辟新的机会。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Heart failure is a leading cause of mortality worldwide. Patients receive symptomatic treatment, and future biologically targeted therapy will depend on the discovery of new pathways that initiate, promote or potentially reverse the onset of heart muscle failure. In this grant application we propose to characterize Sfrp2 an inhibitor of Wnt signaling which, as our preliminary results indicate, is involved in activation and differentiation of cardiac progenitor cells. These studies should open new avenues for the better understanding of the mechanisms of heart failure and may lead to the potential development of novel therapeutic drugs for myocardial injury, hypertrophy and heart failure.