Imaging of the Myocardial Microenvironment to Facilitate Stem Cell Engraftment

描述（由申请人提供）： 细胞治疗有望修复受损心肌。但是，临床试验中的中度和可变功能益处强调需要更好地理解治疗机制和提供心脏功能以外的见解的特定成像技术。通常情况下，只有一小部分移植的细胞移植在受损的心肌，限制了治疗效果，并提供了一个潜在的解释功能的好处的变化。心肌微环境被认为是细胞成功植入的关键因素，并构成了分子成像的合适靶点。 在这项提案中，我们的目标是制定战略，以促进成功的干细胞移植。我们的中心假设是，分子靶向核成像细胞交付前可以表征一个最佳的生物环境，这是支持交付后的细胞植入，从而预测成功的心肌再生。这一假设将在3个具体目标中进行检验。将采用定量核成像技术来表征心肌梗死大鼠模型中的心肌环境以及干细胞植入。将通过系列超声心动图和组织学检查确定治疗结局。 目标1将定义组织灌注，代谢和活力在干细胞输送的目标区域中的作用，以成功植入心脏来源的干细胞，一种具有记录再生潜力的创新细胞类型。目的2将研究粘附分子1v23整合素在靶区域的表达，如通过分子成像确定的，对于成功的心脏干细胞植入的作用。在目标3中，心脏干细胞作为一种较新的细胞类型，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基于干细胞的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，通过指导细胞递送的时机和区域靶向，可以帮助做出治疗决策。该项目的最终目标是基于个体疾病生物学成像来优化细胞治疗效益。 公共卫生相关性： 心脏干细胞治疗被认为是一种非常有前途的修复受损心肌的方法，但目前临床试验中的获益仍不稳定。在这个建议中，分子成像技术的目的是提高细胞治疗，通过提供有关心肌微环境条件，这是最适合干细胞移植的信息。这种生物成像策略有可能指导个体治疗决策，因此与优化干细胞治疗在心脏病临床管理中的益处高度相关。

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.