The SDF1-CXCR4 Axis in Cardiac Homeostasis and Regeneration

描述（由申请人提供）：干细胞可以促进成人心肌细胞的形成，并且这些干细胞也可以参与心脏损伤后的修复，这一发现实现了基于细胞的心脏细胞再生和功能恢复治疗的前景。现在很清楚，心脏具有固有的再生能力，但也很清楚，这种能力是有限的。将间充质干细胞移植到患者体内可引起可重复的功能增加，并为这种治疗方法的潜力提供了见解。迄今为止，对于产生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体内平衡或损伤期间和之后的系统知之甚少。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。我们在心脏中发现了SDF1-CXCR4轴，两者都在肌细胞和成纤维细胞上表达，并与MAPK和AKT信号功能偶联，在体外和体内抗缺血再灌注损伤中发挥生存功能。SDF1和CXCR4基因敲除都是胚胎致死性心脏缺陷。这些新发现为我们的假设提供了基础，即心脏SDF1-CXCR4轴通过对心脏干细胞、肌细胞和成纤维细胞的作用在心脏稳态中发挥作用。SDF1和CXCR4的肌细胞和成纤维细胞表达被认为在心脏干细胞维持和保护（生态位形成）方面具有与骨髓基质细胞和成骨细胞相似的功能。由于SDF1-CXCR4信号的脱敏导致SDF1-CXCR4信号的减弱，该系统在应激或损伤时保护和维持心肌的有效性受到限制。我们建议通过增加受体的数量和/或限制SDF1- CXCR4信号的脱敏来增加这种有效性。以下目的旨在进一步确定SDF1-CXCR4轴在心脏稳态和再生中的作用，并确定通过优化CXCR4信号作为心脏损伤的细胞治疗来增强CSC在心脏再生中的功能。目的1：确定心脏SDF1-CXCR4在维持心肌细胞、肌成纤维细胞和心脏干细胞的心脏稳态中的作用。目的2：确定SDF1-CXCR4信号的脱敏/下调如何限制心脏干细胞的功能。目的3：确定心肌梗死和IR损伤后早期和晚期通过SDF1-CXCR4轴增加心脏干细胞的信号传导和信号传导功效是否有助于增加再生能力。目的4：确定SDF1-CXCR4是否与HGF-cMET和IGF1-IGFR信号系统协同增加对干细胞植入和功能心肌修复至关重要的功能。这项开创性的发现表明，心脏中含有一群干细胞，这些干细胞可以帮助修复受损的心脏，这为心脏修复的细胞治疗提供了新的希望。本提案中描述的研究将促进我们对调节心脏干细胞功能的内在心脏系统及其与心肌和支持细胞的关系的理解并提供机制见解。这些机制研究的结果将为设计新的策略提供动力，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。

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.