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: 7677505
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677505
• 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; 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; 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.

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.