Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart

The mechanistic basis for why inflammation is simultaneously both deleterious and essential for tissue repair is not fully understood. Recently, a new paradigm has emerged: Organs are replete with resident macrophages of embryonic origin distinct from monocyte-derived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities after injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition is a key determinant of cardiac tissue repair. Using a genetic model of cardiomyocyte ablation, we demonstrated that neonatal mice expand a population of embryonic-derived resident cardiac macrophages, which generate minimal inflammation and promote cardiac recovery through cardiomyocyte proliferation and angiogenesis. During homeostasis, the adult heart contains embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by monocyte-derived macrophages that are proinflammatory and lacked reparative activities. Inhibition of monocyte recruitment to the adult heart preserved embryonic-derived macrophage subsets, reduced inflammation, and enhanced tissue repair. These findings indicate that embryonic-derived macrophages are key mediators of cardiac recovery and suggest that therapeutics targeting distinct macrophage lineages may serve as novel treatments for heart failure.There are numerous examples of seemingly contradictory reports claiming that inflammation is both harmful after injury and essential for tissue repair (1). This paradox is well established in models of cardiac injury. Macrophages within the infarcted heart not only drive robust inflammatory responses and pathological left ventricular (LV) remodeling but also are required for the resolution of inflammation and reparative activities, including angiogenesis (2). One proposed explanation for these findings suggests that distinct macrophage populations may mediate inflammatory (M1) and reparative (M2) macrophage behaviors (3). However, the exact identities of these proposed macrophages remain undefined.Paradigm shifting studies have revealed that tissue macrophages represent a heterogeneous population of cells derived from distinct developmental origins (4), including embryonic-derived and adult monocyte-derived subsets (5–8). Consistent with these observations, we have recently reported that the adult heart also contains embryonic-derived and monocyte-derived macrophages (9) with differing recruitment dynamics and gene expression profiles. Although details describing the tissue distribution of embryonic-derived macrophages and their relationship to traditional monocyte-derived macrophages are beginning to emerge, the critical issue of whether macrophages of distinct origin have unique inflammatory, reparative, and immunologic functions remains largely unexplored.Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult, offering an ideal context in which to examine these concepts. After surgical apical resection, cryoablation, or myocardial infarction, neonatal mice efficiently regenerate myocardium (10–13), a process that is dependent on macrophages (14). The precise identity of neonatal macrophages and their relationship to macrophages found in the adult heart is unknown. On the basis of these findings, we hypothesized that distinct macrophage lineages are present in the neonatal and adult heart and explain the repeated observation that the neonatal heart recovers LV structure and function after tissue injury, whereas the adult heart undergoes pathologic remodeling and does not fully recover function.To test these hypotheses, we established an in vivo mouse model of cardiomyocyte injury, using a diphtheria toxin receptor (DTR)-based system. This model provides a simple approach to delivering precise and titratable cardiomyocyte cell death at varying stages of development and also avoids unintended consequences of surgical thoracotomy, including systemic inflammation and cardiac fibrosis (15). Through a combination of flow cytometry, genetic lineage tracing techniques, and depletion studies, we demonstrate that neonatal mice contain a resident macrophage lineage that is derived from the embryo, produces minimal inflammation, and is required for cardiac repair through the promotion of coronary angiogenesis and myocardial proliferation. During homeostasis, the adult heart contained embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by proinflammatory monocytes and monocyte-derived macrophages, which have a limited capacity to promote cardiac repair and, instead, generate inflammation and oxidative stress. We further demonstrate that manipulation of distinct macrophage lineages improves the adult heart’s intrinsic capacity for cardiac repair.