Imaging Cardiac Regeneration with Mesenchymal Stem Cells

描述(由申请人提供)： 由于心脏的再生能力有限，缺血事件往往不仅会导致心肌梗死，还会导致心肌梗死后的重构和充血性心力衰竭的发展。大多数治疗技术的目的是通过恢复血管通畅和减少心肌作功来限制梗塞范围。近年来，骨髓来源的间充质干细胞(MSCs)被移植到梗死心肌中，以再生和修复受损的心肌，以期恢复正常的心功能。由于缺血性心脏病是西方世界发病率和死亡率的最大原因，旨在再生不可逆转损伤的心肌的治疗方法可能会带来巨大的医疗保健效益。然而，MSCs诱导心肌再生的许多机制尚未阐明。最近，我们的团队展示了用磁共振成像(MRI)可见的试剂标记MSCs的能力。利用MRI的高空间和时间分辨率跟踪移植后MSCs的命运的能力，将使我们能够优化方案(例如，注射时间、注射位置和注射方式)，并使用非侵入性技术，如MR标记，研究干细胞移植的治疗反应。最终，干细胞在患者体内的移植将需要MRI等技术，这些技术可以监测非侵入性的组织迁移，并评估对梗死面积和心功能的影响。患者临床移植的另一个问题是，自体骨髓间充质干细胞能否提供与同种异体骨髓间充质干细胞同等程度的植入。由于可以使用类似于血库的细胞培养和冷冻技术来提供随时可用的自体MSCs，因此异基因MSC移植将比自体MSC移植更可取。因此，在这项研究项目中，我们建议在猪心肌梗死模型中使用无创磁共振成像技术确定标记MSC传递的最佳方案。此外，我们将在我们的动物模型中确定用于移植的同种异体骨髓间充质干细胞是否会引起免疫原性反应，从而与自体骨髓间充质干细胞相比降低治疗效果。由于这些研究将在大型动物模型中进行，这些技术将很容易转移到未来对缺血性心脏病患者的研究中。

DESCRIPTION (provided by applicant): Due to the limited regenerative capacity of the heart, an ischemic event often leads not only to myocardial infarction but also to post-infarction remodeling and the development of congestive heart failure. Most therapeutic techniques are aimed at limiting infarct size by restoration of vessel patency and reducing myocardial work. Recently, mesenchymal stem cells (MSCs), derived from bone marrow, have been transplanted in infarcted myocardium to regenerate and repair damaged myocardium with the hope of restoring normal cardiac function. Since ischemic heart disease is the largest cause of morbidity and mortality in the Western world, therapeutic methods designed to regenerate irreversibly injured myocardium could have enormous health care benefits. However, many of the mechanisms of myocardial regeneration from MSCs have not yet been elucidated. Recently, our group has demonstrated the ability to label MSCs with agents that are visible by Magnetic Resonance Imaging (MRI). The ability to track the fate of MSCs after transplantation, using the high spatial and temporal resolution of MRI, will enable us to optimize protocols (e.g., timing of injection, location of injection, and mode of delivery) and study therapeutic response of stem cell transplantation using non-invasive techniques such as MR tagging. Ultimately, the transplantation of stem cells in patients will require techniques, such as MRI, that can monitor noninvasively tissue migration and evaluate the impact on infarct size and cardiac function. Another concern with clinical transplantation in patients is whether autologous MSCs provide the same degree of robust engraftment as allogenic MSCs. Because a readily available supply of autologous MSCs could be provided using cell culture and freezing techniques analogous to blood banks, allogenic MSC transplantation would be preferable to autologous MSC transplantation. Thus, in this research project, we propose to determine the optimal protocols for labeled-MSC delivery using non-invasive MR imaging techniques in a swine model of myocardial infarction. Furthermore, we will determine in our animal model whether the allogenic MSCs used for transplantation elicit an immunogenic response that in turn will decrease therapeutic efficacy compared to autologous MSCs. Because these studies will be developed in a large animal model, these techniques will be readily transferable to future studies in patients with ischemic heart disease.