Cellular Cardiomyoplasty for Chronic Heart Failure

描述（由申请人提供）：使用基于细胞的疗法修复受损心脏组织的热情和实验支持不断积累。由大量临床前数据支持的最有前途的细胞来源之一是骨髓源性间充质干细胞（MSC）。我们已经表明，MSC改善了左前降支冠状动脉闭塞的猪模型中由前壁心肌梗死（MI）诱导的损伤。具有很大的临床相关性，MSC可以作为同种异体移植物施用，并且已经获得FDA批准用于研究急性MI。几个关键的机制问题需要研究，以合理地推进骨髓间充质干细胞作为治疗急性和慢性心脏损伤的临床开发。这项工作计划将研究一系列关于MSC作为心脏修复剂的作用机制的假设。在目标1中，我们将测试MSC通过多种机制刺激心脏修复的假设，包括刺激内源性修复机制。我们将利用完善的Ml猪模型并施用GFP标记的MSC。将使用心脏MRI和多探测器CT监测心脏修复，并将心脏组织提交共聚焦显微镜检查，以定量内源性细胞来源的细胞植入、分化和增殖。目标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同种异体MSC，以确定同种异体细胞作为心脏修复剂是否等同于自体细胞。此外，我们将测试的假设，即间充质干细胞是上级全骨髓单核细胞制剂，最后，我们将评估各种细胞输送方法。在目标3中，我们将在2种已建立的心力衰竭（HF）模型中进行研究-慢性缺血性心肌病和起搏诱导的HF。将使用心肌性能的综合评价（包括心脏磁共振成像（MRI）、血流动力学压力-容积导管插入术和电生理学测试）评估MSC在慢性HF中的疗效。这一目标的结果有可能扩大适合接受细胞肌成形术的患者人群。总之，这些实验将推进使用MSC的细胞肌成形术的翻译和机制理解，并评估这些细胞是否代表了广泛的急性和慢性结构性心脏病的新治疗方法。

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.