Exercise and Stem Cell Engraftment in the Heart Following Myocardial Infarction

描述（由申请人提供）：随着心血管生物学进入心脏病干/祖细胞治疗时代，了解运动如何影响祖细胞生物学和治疗非常重要。 这项提议中概述的实验将首次测试运动是否可以“预处理”梗死后的心肌，以更有效地保留外源性注入的祖细胞。虽然迄今为止的研究表明，基于细胞的治疗可以改善心肌梗死患者的左心室功能，但祖细胞植入率低限制了治疗效果。改善先天性心肌表型的祖细胞归巢，植入和增殖可能会增加基于细胞的治疗的临床潜力。有氧运动是一种特殊的干预措施 改善心肌表型。大量研究表明，运动可以提高心肌缺血再灌注耐受性，减少细胞凋亡，增加心肌血流量，改变各种激素和代谢心肌细胞信号通路。本提案中概述的新实验旨在测试急性有氧运动改善外源性输注的骨髓源性祖细胞（BMC）向梗死的C57 BL/6 J小鼠心脏的归巢和植入的特定假设。我们还将确定运动在多大程度上增强了外源性和内源性细胞库中新心肌细胞的形成。 我们实验室的可行性研究支持这些假设，并且拟议研究的结果将提供关于优化心肌BMC保留和形成新心肌细胞所需的运动“剂量”的关键翻译信息。 这些实验的结果将为转基因小鼠和人类的后续实验奠定基础。

DESCRIPTION (provided by applicant): As cardiovascular biology enters the era of stem/progenitor cell therapy for heart disease, it is important to understand how exercise impacts progenitor cell biology and therapy. Experiments outlined in this proposal will for the first time test whether exercise can "precondition" the post-infarcted myocardium to more effectively retain exogenously-infused progenitor cells. While research to date has shown that cell-based therapy can improve left ventricular function in myocardial infarction, low progenitor cell engraftment rates have limited the efficacy of the treatment. Improving the innate myocardial phenotype for progenitor cell homing, engraftment, and proliferation will likely augment the clinical potential of cell-based therapy. Aerobic exercise is one specific intervention known to improve myocardial phenotype. A host of studies have shown that exercise improves cardiac ischemia-reperfusion tolerance, decreases apoptosis, augments myocardial blood flow, and alters various hormonal and metabolic cardiomyocyte signaling pathways. The novel experiments outlined in this proposal are designed to test the specific hypothesis that acute aerobic exercise improves homing and engraftment of exogenously-infused bone marrow-derived progenitor cells (BMC's) to the infarcted C57BL/6J mouse heart. We will also determine to what extent exercise augments new cardiomyocyte formation from exogenous and endogenous cell pools. Feasibility studies from our laboratory support these hypotheses, and results from the proposed studies will provide crucial translational information regarding the required "dose" of exercise necessary to optimize myocardial BMC retention and form new cardiomyocytes. Results from these experiments will establish the basis for subsequent experiments in transgenic mice and then in humans.