Protection of Ischemic Myocardium

细胞疗法的临床翻译一直受到以下因素的阻碍：1)缺乏对基本机制的了解；2) 临床试验中的结果不明确或不一致。此续期申请的首要目标是 直接解决这两个问题；具体地说，增进我们对 细胞疗法，并开发优化其治疗效果的策略。我们将重点放在心脏 间充质细胞(CMCs)，我们最近获得的一种有希望的新的心脏来源细胞群 发现了这一点，似乎特别适合临床翻译。四个密切相关和密切相关的 相互依存的项目将涉及这一主题的不同方面。项目1(博利)将仔细评估 使用重复治疗以最大化治疗收益，包括临床前的转化性研究 猪模。中心假设是，反复服用CMCs显著增加了 通过重复释放细胞外小泡(EV)的细胞治疗的有益效果。项目2 (Wyoczynski)将阐明免疫细胞在调节细胞治疗和测试的有益效果中的作用 CMC和EVS促进单核细胞募集和修复激活的假说 巨噬细胞，它是修复的内源性媒介。项目3(琼斯)将阐明 间质间质(包括成纤维细胞活化和透明质酸代谢)在修复中的作用 CMC和EVS，并识别和纠正因心力衰竭(HF)导致CMC功能不全的缺陷。这个 最重要的假设是，CMCs通过有利地促进透明质酸代谢来减轻重塑， 它在高频中是有缺陷的。项目4(Bhatnagar)将确定糖尿病如何影响CMC介导的心肌 修复以及如何优化CMC治疗糖尿病心脏。中心假设是糖尿病 通过增加糖酵解来影响CMCs的治疗效果，这改变了旁分泌机制， Sirt1通过减少糖酵解来提高CMC的修复能力。因此，所有四个项目都集中在一起 在CMCS上。这些项目将得到四个核心的支持，这些核心将提供老鼠和猪手术方面的专业知识， 细胞移植、CMC培养和表型、病理学、流式细胞术和细胞分选。这一高度- Focus PPG将由多年来富有成效地合作的调查人员领导。他们悠久的历史 合作的结果是紧密结合的项目，非常适合PPG。在整个过程中 在四个项目中，CMCS的效果将与电动汽车的效果进行系统的比较。这将是第一次 系统研究重复给药的效果以及免疫细胞和基质细胞的作用， 糖酵解和Sirt1在细胞治疗中的有益作用；因此，结果将是全新的。那头猪 研究(3个项目)将为CMC治疗心衰患者的翻译性研究奠定基础。 这种PPG可能会产生颠覆性的新知识，包括两种新的治疗模式(重复 无细胞电动汽车产品的治疗和使用)，其中任何一项本身都将使细胞治疗发生革命性变化。

Clinical translation of cell therapy has been hindered by i) lack of understanding of basic mechanisms, and ii) borderline or inconsistent results in clinical trials. The overarching objective of this renewal application is to directly address these two problems; specifically, to advance our understanding of the mechanism of action of cell therapy and to develop strategies that optimize its therapeutic efficacy. We will focus on cardiac mesenchymal cells (CMCs), a promising new population of heart-derived cells that we have recently discovered and that appears to be particularly suitable for clinical translation. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Bolli) will carefully evaluate the use of repeated treatments to maximize therapeutic benefit, including translational studies in a preclinical porcine model. The central hypothesis is that repeated administrations of CMCs dramatically increase the beneficial effects of cell therapy via repetitive bursts of extracellular vesicle (EV) release. Project 2 (Wysoczynski) will elucidate the role of immune cells in mediating the beneficial effects of cell therapy and test the hypothesis that CMCs and EVs facilitate recruitment of monocytes and activation of reparative macrophages, which are endogenous mediators of repair. Project 3 (Jones) will illuminate the role of the stromal compartment (including fibroblast activation and hyaluronan metabolism) in the reparative actions of CMCs and EVs and identify and correct defects in CMCs rendered incompetent by heart failure (HF). The overarching hypothesis is that CMCs attenuate remodeling by favorably enhancing hyaluronan metabolism, which is defective in HF. Project 4 (Bhatnagar) will determine how diabetes affects CMC-mediated myocardial repair and how CMC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes compromises the therapeutic efficacy of CMCs by increasing glycolysis, which alters paracrine mechanisms, and that Sirt1 improves CMC repair capacity by decreasing glycolysis. Thus, all four Projects focus cohesively on CMCs. These Projects will be supported by four Cores that will provide expertise in mouse and pig surgery, cell transplantation, CMC culture and phenotyping, pathology, flow cytometry, and cell sorting. This highly- focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. Throughout the four Projects, the effects of CMCs will be systematically compared with those of EVs. These will be the first studies to systematically examine the effects of repeated doses and the role of immune and stromal cells, glycolysis, and Sirt1 in the salubrious effects of cell therapy; thus, the results will be entirely new. The pig studies (3 Projects) will lay the groundwork for translational investigations of CMC therapy in patients with HF. This PPG may generate disruptive new knowledge, including two new therapeutic paradigms (repeated treatments and use of cell-free EV products), either of which, in itself, would revolutionize cell therapy.