Imaging mitochondrial function of progenitor cells transplanted to the ischemic myocardium

 描述(由申请人提供)：干细胞(SCs)作为心肌梗死后心肌修复的治疗方法引起了极大的兴趣。然而，干细胞移植到受损心肌后的存活率一直很低，这将限制这些治疗的有益效果。了解干细胞如何与受损的缺血后心肌相互作用将提供关键的见解，可用于优化干细胞的治疗。缺血后心肌的促炎、促凋亡和促纤维化环境造成了一个不利的微环境，影响了移植的干细胞的功能，限制了它们的生存。细胞死亡可由细胞凋亡和/或坏死引起，在这两种情况下，线粒体功能障碍都处于这些事件的中心，其外膜电位失调，导致凋亡/坏死级联反应的启动。因此，线粒体是决定移植后干细胞存活的重要细胞器。首席调查员此前已经证明，报告基因生物发光成像(BLI)可以用于准确、纵向、非侵入性地监测细胞活力。最近，我们开发并验证了一种基于报告基因的成像传感器，用于监测线粒体的生物学特性，并了解移植的干细胞与缺血心肌之间的相互作用。这一建议的假设是，移植的干细胞的线粒体功能，作为缺血后心肌和干细胞之间相互作用的读出，可以无创地监测，并且这种成像策略可以适应临床使用。在目标1中，我们将使用线粒体功能作为干细胞健康状况的指示器，检验缺血后心肌与移植的干细胞之间的相互作用可以无创监测的假设。在目标2中，我们将测试这种线粒体功能监测策略可以应用于心脏病的大型动物模型的假设。在这里，我们将使用分子成像策略来研究干细胞与缺血心肌之间的相互作用。此外，我们还将为这些策略的临床翻译提供概念验证。

 DESCRIPTION (provided by applicant): There is significant interest in the use of stem cells (SCs) as a therapy for myocardial repair after myocar- dial infarction. However, the survival of SCs, after transplantation to the injured myocardium, has been poor and will limit the beneficial effect of these therapies. Understanding how SCs interact with the injured post- ischemic myocardium will provide critical insight that can be used to optimize SC therapies. The pro-inflammatory, pro-apoptotic, and pro-fibrotic milieu of the post-ischemic myocardium creates a hostile microenvironment that affects the function of transplanted SCs, limiting their survival. Cell death can occur due to apoptosis and/or necrosis, and in both scenarios mitochondrial dysfunction has been placed at the center of these events, with dysmodulation of their outer membrane potential, leading to initiation of the apoptotic/necrotic cascade. Thus, the mitochondria appear as a critical organelle that can determine the sur- vival of transplanted SCs. The Principal Investigator has previously shown that reporter gene bioluminescence imaging (BLI) can be used to accurately and longitudinally monitor cell viability non-invasively. Recently, we have developed and validated a reporter gene-based imaging sensor to monitor the biology of the mitochondria, and understand the interaction between transplanted SCs and the ischemic myocardium. The hypothesis of this proposal is that the mitochondrial function of transplanted SCs, as a read-out of the interaction between the post-ischemic myocardium and SCs, can be monitored non-invasively, and that such imaging strategies can be adapted for clinical use. In Aim 1 we will test the hypothesis that the interaction between the post-ischemic myocardium and transplanted SCs can be monitored non-invasively, using mitochondrial function as an indicator of the health of SCs. In Aim 2 we will test the hypothesis that this mitochondrial function monitoring strategy can be applied to a large animal model of cardiac disease. Here, we will use molecular imaging strategies to study the interaction between SCs and the ischemic myocardium. Furthermore, we will provide proof-of-concept for the clinical translation of these strate- gies.