Cellular Cardiomyoplasty for Chronic Heart Failure

描述(申请人提供)：对使用基于细胞的疗法修复受损的心脏组织有越来越多的热情和实验支持。大量临床前数据支持的最有前途的细胞来源之一是骨髓间充质干细胞(MSCs)。在猪左前降支闭塞模型中，MSCs可改善前壁心肌梗死(ML)所致的损伤。具有重要临床意义的是，MSCs可以作为同种异体移植物使用，并已获得FDA批准用于急性ML的研究。为了合理推进骨髓间充质干细胞作为急慢性心脏损伤治疗方法的临床发展，需要对几个关键的机制问题进行研究。这项工作计划将检验一系列关于骨髓间充质干细胞作为心脏修复介质的作用机制的假设。在目标1中，我们将验证MSCs通过几种机制刺激心脏修复的假设，包括刺激内源性修复机制。我们将利用一种成熟的猪ML模型，并应用GFP标记的MSCs。心脏修复将使用心脏核磁共振和多探测器CT进行监测，心脏组织将被提交给共焦显微镜，以量化细胞植入、分化和内源性细胞来源的增殖。AIM 2将解决有关MSC治疗的几个关键问题。我们将在功能和分子/细胞水平上比较自体和异体间充质干细胞，以确定同种异体细胞是否等同于作为心脏修复试剂的自体细胞。此外，我们将检验MSCs优于全骨髓单核细胞制剂的假设，最后我们将评估各种细胞输送方法。在目标3中，我们将在两个已建立的心力衰竭(HF)模型上进行研究--慢性缺血性心肌病和起搏诱发心力衰竭。MSC对慢性心衰的疗效将通过包括心脏磁共振成像(MRI)、血流动力学压力-容量插管和电生理测试在内的心肌表现的综合评估来评估。这一目标的结果有可能扩大有资格接受细胞肌肉成形术的患者群体。总之，这些实验将促进对使用MSCs进行细胞肌肉成形术的翻译和机制方面的理解，并评估这些细胞是否代表着一种治疗各种急、慢性结构性心脏病的新方法。

DESCRIPTION (provided by applicant): There is accumulating enthusiasm and experimental support for repairing damaged cardiac tissue using cell- based therapies. One of the most promising cell sources, supported by substantial pre-clinical data, is bone marrow derived mesenchymal stem cells (MSCs). We have shown that MSCs ameliorate the damage induced by anterior wall myocardial infarction (Ml) in a pig model of left anterior descending coronary artery occlusion. Of great clinical relevance, MSCs may be administered as an allogeneic graft and have received FDA approval to be studied for acute Ml. Several critical mechanistic issues require study in order to rationally advance the clinical development of MSCs as a therapy for acute and chronic cardiac injury. This program of work will examine a series of hypotheses regarding the mechanism of action of MSCs as an agent of cardiac repair. In aim 1, we will test the hypothesis that MSCs stimulate cardiac repair by several mechanisms, including stimulation of endogenous repair mechanisms. We will utilize a well-established porcine model of Ml and administer GFP labeled MSCs. Cardiac repair will be monitored with cardiac MRI and multi-detector CT and cardiac tissue will be submitted to confocal microscopy to quantify cell engraftment, differentiation, and the proliferation of endogenous cell sources. Aim 2 will address several critical issues regarding MSC therapy. We will compare autologous and allogeneic MSCs both at functional and molecular/cellular levels to address whether allogeneic cells are equivalent to autologous cells as an agent of cardiac repair. Additionally, we will test the hypothesis that MSCs are superior to whole bone marrow mononuclear preparations, and finally we will assess various cell delivery methods. In aim 3, we will perform studies in 2 established heart failure (HF) models - chronic ischemic cardiomyopathy and pacing induced HF. MSC efficacy in chronic HF will be assessed using comprehensive evaluation of myocardial performance including cardiac magnetic resonance imaging (MRI), hemodynamic pressure-volume catheterization, and electrophysiology testing. The results of this aim have the potential to broaden the patient population eligible to receive cellular myoplasty. Together, these experiments will advance the translational and mechanistic understanding of cellular myoplasty using MSCs and evaluate whether these cells represent a novel treatment for a wide range of acute and chronic structural heart disease.