Cellular Cardiomyoplasty for Chronic Heart Failure

描述（由申请人提供）：在慢性缺血性心脏病的细胞疗法的理解和转化进展方面取得了重大进展，慢性缺血性心脏病是一种影响约500万美国人的疾病。 我们利用该奖项的第一个资助期开发了以进行性心室重构为特征的缺血性心肌病的复杂猪模型。 使用这个模型，我们已经测试了几种基于细胞的治疗策略，收集了主要的机制见解，并开发了足够的临床前数据，以便能够启动临床试验。重要的是，我们发现间充质干细胞（MSC）在受损猪心脏中的植入和分化伴随着1）与宿主细胞的间隙连接形成，2）刺激内源性心脏干细胞（CSC）增殖和分化，3）在先前慢性缺血性功能障碍的心肌区域中持续的逆向重塑和收缩恢复。在初步研究结果中，我们还表明，MSC与CSC的组合在减少梗死面积方面具有显著更大的功效。在此续期申请中，我们建议识别 利用我们建立的猪模型，对缺血性心肌病这种新的基于细胞的治疗策略进行分子基础研究。因此，我们提出了一系列的三个目标，旨在测试新的机制假设MSC和CSC为基础的心脏再生。 我们建议1）建立自体CSC和MSC组合导致的改善的梗死瘢痕减少的潜在机制，2）评估通过连接蛋白43（Cx43）介导的间隙连接的细胞-细胞通信对心脏再生的影响，和3）评估细胞-细胞相互作用和β-内酰胺酶和/或遗传修饰的CSC用于缺血性心肌病中心肌修复的功效。这些研究将继续我们的工作轨迹，旨在获得最可靠的临床前数据，以扩大我们对慢性缺血性心脏病细胞治疗机制的知识基础。拟议的研究是及时的，有必要的，并且可能通过解决大量存在进行性心力衰竭、终身残疾、心源性猝死和复发性住院风险的患者人群中未满足的需求而产生重大的健康影响。所采用的方法得到了我们小组的充分验证，包括体外和体内实验模型和有效的细胞递送系统以及我们小组目前使用的最先进的成像策略。我们的机制研究计划具有很高的转化价值，并且非常重要，因为细胞治疗提供了 再生新的心肌，并减少因心肌梗死愈合而导致左心室功能不全患者的心力衰竭进展。总之，这些目标将促进我们对慢性缺血性心脏病细胞治疗机制的理解，特别强调细胞联合治疗的影响。 类型和调节的分子机制，可以有加和或协同性能，从而提高缺血性心肌病的细胞疗法的疗效和持久性。

DESCRIPTION (provided by applicant): Major progress has been made in the understanding and translational advancement of cell-based therapeutics for chronic ischemic heart disease, a condition affecting approximately 5 million Americans. We have used the first funding period of this award to develop sophisticated porcine models of ischemic cardiomyopathy characterized by progressive ventricular remodeling. Using this model we have tested several strategies for cell-based therapeutics, gleaned major mechanistic insights, and developed sufficient preclinical data to be able to initiate clinical trials. Importantly, we showed that engraftment and differentiation of mesenchymal stem cells (MSCs) in the injured porcine heart was accompanied by 1) gap junction formation with host cells, 2) stimulation of endogenous cardiac stem cell (CSC) proliferation and differentiation and 3) sustained reverse remodeling and contractile restoration in myocardial areas of prior chronic ischemic dysfunction. In preliminary findings, we also showed that combining MSCs with CSCs leads to substantially greater efficacy at infarct size reduction. In this renewal application, we propose to identify the molecular underpinnings of this novel cell- based therapeutic strategy for ischemic cardiomyopathy using our established porcine model. Accordingly, we propose a series of three aims designed to test novel mechanistic hypotheses regarding MSC and CSC-based cardiac regeneration. We propose to 1) establish the mechanisms underlying the improved infarct scar reduction resulting from a combination of autologous CSCs and MSCs, 2) assess the impact of cell-cell communication by connexin 43 (Cx43)-mediated gap junctions on cardiac regeneration, and 3) assess the cell- cell interaction and efficacy of pharmacologically and/or genetically modified CSCs for myocardial repair in ischemic cardiomyopathy. These studies will continue our trajectory of work designed to obtain the most robust preclinical data possible to enlarge our knowledge base of the mechanisms underlying cell-based therapy for chronic ischemic heart disease. The proposed studies are timely, warranted, and could have a major health impact by addressing an unmet need in a large population of patients at risk for progressive heart failure, lifelong disability, sudden cardiac death, and recurrent hospitalizations. The approaches employed are well validated by our group and include in vitro and in vivo experimental models and efficient cell delivery systems and state of the art imaging strategies currently in use by our group. Our mechanistic research program has high translational value and is highly significant, as cellular therapy offers the potential to regenerate new myocardium and decrease progression of heart failure in patients with left ventricular dysfunction due to healed myocardial infarction. Together, these aims will advance our understanding of the mechanisms underlying cell- based therapy for chronic ischemic heart disease, with specific emphasis placed upon the impact of a combination of cell types and modulation of molecular mechanisms that can have additive or synergistic properties, thereby enhancing the efficacy and durability of cell therapy for ischemic cardiomyopathy.