Macrophages trigger cardiomyocyte proliferation by increasing epicardial vegfaa expression during larval zebrafish heart regeneration

• Published in: Developmental cell Vol. 57; no. 12; pp. 1512 - 1528.e5
• Main Authors: Bruton, Finnius A., Kaveh, Aryan, Ross-Stewart, Katherine M., Matrone, Gianfranco, Oremek, Magdalena E.M., Solomonidis, Emmanouil G., Tucker, Carl S., Mullins, John J., Lucas, Christopher D., Brittan, Mairi, Taylor, Jonathan M., Rossi, Adriano G., Denvir, Martin A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.06.2022; Cell Press
• Subjects: epicardium; heart; macrophages; notch; regeneration; repair; vegf; zebrafish; repair; macrophages; regeneration; epicardium; vegf; notch; zebrafish; heart
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.05.014

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. [Display omitted] •Heart regeneration in larval zebrafish is characterized in detail•Macrophage ablation blocks cardiomyocyte proliferation after cardiac injury•Macrophages synapse with epicardial cells and promote their proliferation•Epicardial Vegfaa drives cardiomyocyte proliferation during cardiac regeneration In this study, Bruton et al. test the requirement for macrophages for cardiac regeneration in larval zebrafish, finding macrophages to be necessary for cardiomyocyte proliferation via the activation of the epicardium. The identification of this macrophage-dependent mechanism of cardiac regeneration supports immunomodulation as a promising strategy for enhancing mammalian cardiac repair.