MACROPHAGE HETEROGENEITY IN HEART FAILURE PROGRESSION AND CARDIAC RECOVERY

项目摘要/摘要 扩张型和缺血性心肌病是心力衰竭和心血管疾病的常见原因 全球范围内的死亡率。虽然里程碑式的临床试验导致了有效的心力衰竭的建立 治疗和临床结果的改善，死亡率居高不下，许多患者最终经历了 疾病进展，突出了临床上未得到满足的确定新治疗方法的需求。心肌恢复是 对于数量不多但数量可观的心力衰竭患者来说，这是一个日益得到认可的结果。病人 那些经历了心肌恢复的人的生活质量和生存能力都得到了改善。基于这些观察， 心肌恢复是一个可实现的结果，也是一个潜在的新的治疗目标。然而， 决定恢复的机制，并最终确定为什么一些患者在 其他经历疾病进展的人定义得很模糊。 值得注意的是，心力衰竭儿童表现出明显更强的心肌梗死能力。 与成年人相比，恢复得更好。在此背景下，为了剖析介导心肌恢复的机制，我们 建立了一个急性心力衰竭的小鼠模型，并成功地概括了观察到的 儿科心脏具有强大的组织修复和功能恢复能力。从机制上讲，我们发现 受伤的儿童和成人心脏有不同的原始和确定的巨噬细胞亚群，并且 这些细胞决定了为什么儿童小鼠和成年小鼠表现出不同的病理反应和能力 组织损伤后恢复。总体而言，这些实验揭示了一种以前未被认识到的 先天免疫系统的复杂性，并挑战了所有巨噬细胞都是 来源于单核细胞祖细胞。虽然这些观察发人深省，并提供了证据 不同的巨噬细胞谱系有能力不同地协调心脏组织修复的原理 以及心力衰竭的进展，目前尚不清楚这些概念如何应用于慢性心力衰竭。 这一提议的首要目标是检验这样一种假设，即慢性衰竭的老鼠和 人类心脏含有进化上保守的巨噬细胞亚群，来自不同的发育阶段 分别协调心脏组织修复和不良重塑的起源。具体来说，我们 假设原始巨噬细胞通过刺激组织修复来保护心脏功能，而 最终的单核细胞来源的巨噬细胞通过炎症促进心力衰竭的进展，其结果 附带损害，以及随之而来的不利重建。临床上，修复性和非修复性的鉴定 炎症性心肌巨噬细胞群及其信号通路的阐明 发挥它们的作用可能提供必要的信息，以开发新的治疗策略，以限制 促进疾病进展，促进衰竭心脏的恢复。

PROJECT SUMMARY/ABSTRACT Dilated and ischemic cardiomyopathies represent prevalent causes of heart failure and cardiovascular mortality worldwide. While landmark clinical trials have led to the establishment of effective heart failure therapies and improved clinical outcomes, mortality rates remain high and many patients ultimately experience disease progression, highlighting the clinically unmet need to identify novel treatments. Myocardial recovery is an increasingly recognized outcome for a small but significant number of patients with heart failure. Patients who experience myocardial recovery have improved quality of life and survival. Based on these observations, myocardial recovery represents an achievable outcome and a potential new therapeutic target. However, the mechanisms that dictate recovery and ultimately determine why some patients recover cardiac function while others experience disease progression are poorly defined. Remarkably, children with heart failure demonstrate a significantly greater capacity for myocardial recovery compared to adults. To dissect the mechanisms that mediate myocardial recovery in this context, we developed a mouse model of acute heart failure and successfully recapitulated the observation that the pediatric heart has a robust capacity for tissue repair and functional recovery. Mechanistically, we discovered that the injured pediatric and adult heart harbor distinct primitive and definitive macrophage subsets and that these cells govern why pediatric and adult mice display differing pathologic responses and capacities to recover following tissue injury. Collectively, these experiments uncovered a previously unrecognized complexity within the innate immune system and have challenged the paradigm that all macrophages are derived from monocyte progenitors. While these observations are thought provoking and provide proof of principle that distinct macrophage lineages have the capacity to differentially orchestrate cardiac tissue repair and heart failure progression, it is unclear how these concepts apply to the chronically failing heart. The overarching goal of this proposal is to test the hypothesis that the chronically failing mouse and human heart contains evolutionarily conserved macrophage subsets derived from distinct developmental origins that orchestrate cardiac tissue repair and adverse remodeling, respectively. Specifically, we hypothesize that primitive macrophages preserve cardiac function by stimulating tissue repair, whereas definitive monocyte-derived macrophages promote heart failure progression through inflammation, resultant collateral damage, and subsequent adverse remodeling. Clinically, the identification of reparative and inflammatory cardiac macrophage populations and elucidation of the signaling pathways by which these cells exert their effects is likely to provide the necessary information to develop novel therapeutic strategies to limit disease progression and promote recovery of the failing heart.