Sfrp2 and Cardiac Progenitor Cells in Regenerative Response to Ischemic Injury

Sfrp2 和心脏祖细胞对缺血性损伤的再生反应

• 批准号: 8786586
• 负责人: Victor J Dzau
• 金额: $ 48.32万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786586
• 关键词: Acute; Address; Adult; Apoptosis; Applications Grants; Biochemical; Biological Models; Biology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Lineage; Cell Proliferation; Cells; Data; Development; Excision; Failure; Felis catus; Fibrosis; Future; Galactosidase; Genetic; Genomic approach; Heart; Heart failure; Hypertrophy; In Vitro; Infarction; Injection of therapeutic agent; Injury; Label; Laboratories; Lead; Maps; Mediating; Mediator of activation protein; Monitor; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Nature; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Process; Proteins; Proto-Oncogene Protein c-kit; Protocols documentation; Regenerative Medicine; Regenerative response; Regulation; Reporter; Research Proposals; Role; Signal Pathway; Signal Transduction; Staging; Stem cell transplant; Stem cells; Tamoxifen; Testing; Therapeutic; Tomatoes; Transgenic Mice; Transgenic Organisms; Troponin T; Wound Healing; angiogenesis; cardiac regeneration; human SFRP4 protein; in vivo; inhibitor/antagonist; insight; mortality; novel; novel therapeutics; progenitor; promoter; regenerative; repaired; stem cell differentiation; targeted treatment

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.

多项研究表明，分泌型卷曲相关蛋白 2 (Sfrp2) 是一种 Wnt 通路抑制剂，是心肌伤口修复的关键介质 并已被证明可以抑制心肌细胞凋亡、诱导血管生成和 抑制纤维化。在一些模型系统中，Sfrp2 是分化的调节因子 目前还没有研究直接阐明 Sfpr2 在 心肌细胞更新和 Sfpr2 在心脏祖细胞 (CPC) 中的作用 激活、增殖和分化仍有待阐明。这 CPC扩张和分化的监管是根本性的，但尚不明确 心血管生物学和再生医学方面。我们的初步 体外和体内研究表明 CPC 对 Wnt/Sfrp2 有反应 发信号。我们的数据表明 Sfrp2 抑制典型的 Wnt3a 信号传导并且 增强成人 c-Kit+/Sca1+ CPC 的分化。因此，Sfrp2 的作用 通过潜在的 Sfpr2/Wnt 相互作用调节成人心肌细胞更新 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 经典通路，是心脏祖细胞的关键调节因子 增殖和谱系规范。为了检验这个假设，使用培养 CPC，我们将在体外研究 Sfpr2 和 Wnt3a 对 CPC 的重要性 增殖和分化，并阐明 Wnt/b-catenin 的作用 规范的信号通路。在体内，我们将通过评估来扩展这些研究 通过检查 Sfrp2 对心肌细胞更新的影响 内生的CPC命运。我们将使用遗传命运图谱研究和谱系 用于检查内源性细胞增殖和激活的追踪方案 心脏干细胞，这些细胞分化为心肌细胞和 确定 Sfrp2 在这些过程中的作用，我们将询问 Wnt/b-连环蛋白经典信号通路在介导 Sfrp2 对体内 CPC 的影响。在本研究计划结束时，我们将 表征了 Sfrp2 信号在成体心脏干细胞中的作用 提供有关调节这些细胞和开放途径的新见解 关于它们的离体或体内调节用于治疗的新机会 目的。

项目成果

Lung stem and progenitor cells.

肺茎和祖细胞。

• DOI: 10.1159/000346500
• 发表时间: 2013
• 期刊: Respiration; international review of thoracic diseases
• 作者: Ardhanareeswaran K;Mirotsou M
• 通讯作者: Mirotsou M