The SDF1-CXCR4 Axis in Cardiac Homeostasis and Regeneration

SDF1-CXCR4 轴在心脏稳态和再生中的作用

• 批准号: 8131612
• 负责人: GREGG ROKOSH
• 金额: $ 37万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131612
• 关键词: Activities of Daily Living; Acute; Address; Adult; Area; Arrestins; Attenuated; Bone Marrow; CXCR4 Receptors; CXCR4 gene; Cardiac; Cardiac Myocytes; Cell Maintenance; Cell Therapy; Cell physiology; Cells; Chemotactic Factors; Chemotaxis; Chronic; Cicatrix; Clear Cell; Congenital Heart Defects; Coupled; Cytoprotection; Disease; Down-Regulation; Effectiveness; Embryo; Engraftment; Environment; Fibroblasts; Functional disorder; G-Protein-Coupled Receptors; GRK6 gene; GTP-Binding Protein Regulators; GTP-Binding Proteins; GTPase-Activating Proteins; Growth Factor Receptors; Heart; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Homing; IGF1 gene; IGF1R gene; In Vitro; Infarction; Infection; Inflammatory; Injury; Ischemia; Knock-out; Knockout Mice; Lead; MAP Kinase Gene; Maintenance; Mediating; Mesenchymal Stem Cell Transplantation; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Myofibroblast; Natural regeneration; Osteoblasts; Patients; Perception; Phosphotransferases; Play; Process; Proto-Oncogene Proteins c-akt; Rattus; Recovery of Function; Recruitment Activity; Reperfusion Injury; Reperfusion Therapy; Research; Role; Seminal; Signal Transduction; Site; Stem cells; Stress; Stromal Cell-Derived Factor 1; Stromal Cells; Supporting Cell; System; Testing; Therapeutic; Tissues; Transgenic Organisms; Transplantation; adult stem cell; attenuation; autocrine; base; biological adaptation to stress; biological systems; cell type; chemokine; desensitization; design; flexibility; improved; in vivo; injured; insight; novel; novel strategies; novel therapeutics; overexpression; paracrine; progenitor; protein function; receptor; regenerative; repaired; residence; response; response to injury; stem cell niche; stem cell population; therapy development; tissue regeneration; trafficking

DESCRIPTION (provided by applicant): The prospect of a cell based therapy for cellular regeneration and functional recovery of the heart was realized with the discovery that stem cells can contribute to myocyte formation in the adult and that these stem cells may also participate in the repair of the heart after injury. It is now clear the heart has inherent regenerative capacity however it is also clear that this capacity is limited. Transplantation of mesenchymal stem cells into patients evokes a reproducible increase in function and provides insight into the potential of this therapeutic approach. To date, little is known of the systems that create and maintain the inherent cardiac stem cells (CSC) and how they participate in day to day function and homeostasis or during and after injury. Stromal cell derived factor 11 (SDF1), and its receptor, CXCR4 are key components of the biological system that regulates hematopoiesis and hematopoietic stem cells. We have found this SDF1-CXCR4 axis in the heart and both are expressed on myocytes and fibroblasts and are functionally coupled to MAPK and AKT signaling that serves a survival function in vitro and in vivo against ischemia reperfusion injury. Both SDF1 and CXCR4 knockouts are embryonic lethal with cardiac defects. These novel findings serve to provide the basis for our hypothesis, that the cardiac SDF1-CXCR4 axis plays a role in cardiac homeostasis through the action on cardiac stem cells, myocytes, and fibroblasts. Myocyte and fibroblast expression of SDF1 and CXCR4 are proposed to serve a similar function for cardiac stem cell maintenance and protection (niche formation) as stromal and osteoblasts do in the bone marrow. The effectiveness of this system in protecting and maintaining the myocardium with stress or injury is limited due to attenuated SDF1-CXCR4 signaling by desensitization of SDF1-CXCR4 signaling. We propose this effectiveness may be increased by increasing the number of receptors and/or limiting desensitization of SDF1- CXCR4 signaling. The following Aims seek to further define the role of the SDF1-CXCR4 axis in cardiac homeostasis and regeneration and to determine how CSC function in cardiac regeneration can be enhanced through optimization of CXCR4 signaling as a cell based therapy in cardiac injury. Aim 1: To determine the role that cardiac SDF1-CXCR4 plays in maintaining cardiac homeostasis in myocyte, myofibroblast, and cardiac stem cells. Aim 2: To determine how desensitization/downregulation of SDF1-CXCR4 signaling limits the functionality of cardiac stem cells. Aim 3: To determine whether increasing signaling and signaling efficacy through the SDF1-CXCR4 axis in cardiac stem cells facilitates increased regenerative capacity by administration early and late after MI and IR injury. Aim 4: To determine whether SDF1-CXCR4 synergizes with HGF-cMET and IGF1-IGFR signaling systems to increase functions critical to stem cell engraftment and repair of functional myocardium. The seminal finding that the heart contains a population of stem cells that can contribute to repair of the injured heart has provided new hope for a cell based therapy for cardiac repair. The research described in this proposal will advance our understanding of and provide mechanistic insight into inherent cardiac systems that regulate the function of cardiac stem cells and their relationship with cardiac muscle and supporting cells. Results from these mechanistic studies will provide the impetus to design novels strategies to overcome inherent limitations of cardiac stem cell participation in cardiac regeneration after cardiac injury or with disease.

描述（由申请人提供）：通过发现干细胞可以在成年人中有助于肌细胞形成的基于细胞再生和功能恢复的基于细胞再生和功能恢复的前景，并且这些干细胞也可以在受伤后的心脏修复中参与。现在很明显，心脏具有固有的再生能力，但是很明显，这种能力是有限的。间充质干细胞移植到患者中会引起可再现的功能增加，并洞悉这种治疗方法的潜力。迄今为止，对创建和维持固有心脏干细胞（CSC）的系统以及它们如何参与日常功能和稳态或受伤期间和后期。基质细胞衍生因子11（SDF1）及其受体CXCR4是调节造血和造血干细胞的生物系统的关键组成部分。我们已经在心脏中发现了SDF1-CXCR4轴，并且两者都在心肌细胞和成纤维细胞上表达，并在功能上与MAPK和AKT信号耦合，该信号在体外和体内具有抗缺血再灌注损伤。 SDF1和CXCR4敲除均具有心脏缺陷的胚胎致死。这些新颖的发现为我们的假设提供了基础，即通过对心脏干细胞，肌细胞和成纤维细胞的作用，心脏SDF1-CXCR4轴在心脏稳态中起作用。 SDF1和CXCR4的心肌细胞和成纤维细胞表达被提出与骨髓中的基质和成骨细胞一样，在心脏干细胞维持和保护（小裂形成）方面具有类似的功能。由于SDF1-CXCR4信号传导的脱敏，该系统在应激或损伤中保护和维持心肌施加压力或损伤的有效性受到限制。我们建议通过增加受体数量和/或限制SDF1-CXCR4信号传导的脱敏来提高这种有效性。以下目的旨在进一步定义SDF1-CXCR4轴在心脏稳态和再生中的作用，并通过优化CXCR4信号传导作为心脏损伤中的细胞疗法来确定CSC在心脏再生中的功能如何增强。目的1：确定心脏SDF1-CXCR4在维持心肌细胞，肌纤维细胞和心脏干细胞中的心脏稳态方面发挥的作用。目标2：确定SDF1-CXCR4信号传导的脱敏/下调如何限制心脏干细胞的功能。 AIM 3：确定通过SDF1-CXCR4轴在心脏干细胞中提高信号传导和信号传导功效是否会促进MI和IR损伤后的早期和晚期通过给药增加的再生能力。目标4：确定SDF1-CXCR4是否与HGF-CMET和IGF1-IGFR信号系统协同作用，以增加对干细胞植入和功能心肌修复至关重要的功能。心脏的开创性发现含有大量的干细胞，可以促进受伤的心脏修复，这为基于细胞的心脏修复治疗提供了新的希望。该提案中描述的研究将提高我们对固有心脏系统的理解并提供机械洞察，这些心脏系统调节心脏干细胞的功能及其与心肌和支持细胞的关系。这些机械研究的结果将为设计小说策略提供动力，以克服心脏干细胞参与心脏损伤或疾病后心脏再生的固有局限性。