Cardiac injury leads to the loss of cardiomyocytes, which are rapidly replaced by the proliferation of the surviving cells in zebrafish, but not in mammals. In both the regenerative zebrafish and non-regenerative mammals, cardiac injury induces a sustained macrophage response. Macrophages are required for cardiomyocyte proliferation during zebrafish cardiac regeneration, but the mechanisms whereby macrophages facilitate this crucial process are fundamentally unknown. Using heartbeat-synchronized live imaging, RNA sequencing, and macrophage-null genotypes in the larval zebrafish cardiac injury model, we characterize macrophage function and reveal that these cells activate the epicardium, inducing cardiomyocyte proliferation. Mechanistically, macrophages are specifically recruited to the epicardial-myocardial niche, triggering the expansion of the epicardium, which upregulates vegfaa expression to induce cardiomyocyte proliferation. Our data suggest that epicardial Vegfaa augments a developmental cardiac growth pathway via increased endocardial notch signaling. The identification of this macrophage-dependent mechanism of cardiac regeneration highlights immunomodulation as a potential strategy for enhancing mammalian cardiac repair.

心脏损伤导致心肌细胞的损失，这些细胞迅速被斑马鱼中存活细胞的增殖所取代，但在哺乳动物中则不然。在再生斑马鱼和非再生哺乳动物中，心脏损伤会诱导持续的巨噬细胞反应。斑马鱼心脏再生过程中心肌细胞增殖需要巨噬细胞，但巨噬细胞促进这一关键过程的机制基本上是未知的。在斑马鱼幼虫心脏损伤模型中使用心跳同步实时成像、RNA 测序和巨噬细胞无效基因型，我们描述了巨噬细胞的功能，并揭示这些细胞激活心外膜，诱导心肌细胞增殖。机械地，巨噬细胞被专门招募到心外膜-心肌小生境，vegfaa表达诱导心肌细胞增殖。我们的数据表明，心外膜 Vegfaa 通过增加心内膜切迹信号来增强发育性心脏生长途径。这种心脏再生的巨噬细胞依赖性机制的鉴定突出了免疫调节作为增强哺乳动物心脏修复的潜在策略。