Imaging of the Myocardial Microenvironment to Facilitate Stem Cell Engraftment

描述(由申请人提供)： 项目摘要细胞疗法在修复受损心肌方面前景看好。但是，在临床试验中，适度和可变的功能益处强调需要更好地了解治疗机制，以及需要特定的成像技术，以提供心脏功能以外的见解。通常，只有一小部分移植细胞植入受损心肌，限制了治疗效果，并为功能益处的多样性提供了潜在的解释。心肌微环境被认为是细胞成功植入的关键因素，也是分子成像的合适靶点。在这项提案中，我们的目标是开发促进干细胞成功植入的策略。我们的中心假设是，在细胞交付之前，分子靶向的核成像可以表征支持细胞在交付后植入的最佳生物环境，从而预测成功的心肌再生。这一假设将在三个具体目标上得到检验。定量核成像技术将被用来表征心肌环境和干细胞在心肌梗死大鼠模型中的植入。治疗结果将通过系列超声心动图和组织学检查来确定。目标1将确定组织灌流、新陈代谢和活性在干细胞输送靶区的作用，以成功植入心脏来源的干细胞，这是一种已证实具有再生潜力的创新细胞类型。目的2研究分子成像确定的黏附分子1v23整合素在靶区的表达对心脏干细胞成功植入的作用。在目标3中，心脏干细胞作为一种新的细胞类型，将在最佳成像定义的微环境条件下与建立时间较长的间充质干细胞进行比较。这些研究将为生物环境对干细胞心肌再生成功的贡献提供独特的新见解。更重要的是，他们还将提供成像技术，通过指导细胞输送的时机和区域靶向来帮助治疗决策。该项目的最终目标是基于对个别疾病生物学的成像来优化细胞治疗效益。 公共卫生相关性： 项目简介/相关性心脏干细胞治疗被认为是修复受损心肌的一种非常有前途的方法，但临床试验的益处目前仍不确定。在这项建议中，引入了分子成像技术，旨在通过提供关于最适合干细胞植入的心肌微环境条件的信息来改进细胞治疗。这样的生物成像策略有可能指导个人的治疗决策，因此对于优化干细胞治疗在心脏病临床管理中的好处具有高度相关性。

DESCRIPTION (provided by applicant): Project Summary Cell therapy is promising for repair of damaged myocardium. But moderate and variable functional benefits in clinical trials emphasize the need for a better understanding of therapeutic mechanisms and for specific imaging techniques which provide insights beyond cardiac function. Frequently, only a small fraction of transplanted cells engrafts in injured myocardium, limiting therapeutic efficacy and providing a potential explanation for the variability of functional benefits. The myocardial microenvironment is considered to be a critical contributor to successful cell engraftment and constitutes a suitable target for molecular imaging. In this proposal, we aim at developing strategies to facilitate successful stem cell engraftment. Our central hypothesis is that molecular-targeted nuclear imaging prior to cell delivery can characterize an optimal biologic environment which is supportive of cell engraftment after delivery, and thus predictive of successful myocardial regeneration. This hypothesis will be tested in 3 specific aims. Quantitative nuclear imaging techniques will be employed to characterize both, myocardial environment, as well as stem cell engraftment in a rat model of myocardial infarction. Therapy outcome will be defined by serial echocardiography and histologic workup. Aim 1 will define the role of tissue perfusion, metabolism and viability in the target area of stem cell delivery, for successful engraftment of cardiac-derived stem cells, an innovative cell type with documented regenerative potential. Aim 2 will investigate the role of expression of the adhesion molecule 1v23 integrin in the target area, as determined by molecular imaging, for successful cardiac stem cell engraftment. In aim 3, cardiac stem cells as a newer cell type will then be compared with the longer established mesenchymal stem cells under conditions of optimal imaging-defined microenvironmental conditions. These studies will provide unique new insights into the contribution of the biologic environment to the success of stem cell based myocardial regeneration. More importantly, they will also provide imaging techniques which may assist in therapeutic decision making by guiding the timing and regional targeting of cell delivery. The ultimate goal of the project is to optimize cell therapeutic benefit based on imaging of individual disease biology. PUBLIC HEALTH RELEVANCE: Project Narrative / Relevance Cardiac stem cell therapy is considered to be a very promising approach for repair of damaged myocardium, but the benefit in clinical trials is currently still variable. In this proposal, molecular imaging techniques are introduced which aim at improving cell therapy by providing information about myocardial microenvironmental conditions which are most suitable for stem cell engraftment. Such biologic imaging strategies have the potential to guide individual therapeutic decisions, and are thus highly relevant to optimize the benefit of stem cell therapy in the clinical management of heart disease.