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

Bruton, F. A. et al. (2022) Macrophages trigger cardiomyocyte proliferation by increasing epicardial vegfaa expression during larval zebrafish heart regeneration. Developmental Cell, 57(12), 1512-1528.e5. (doi: 10.1016/j.devcel.2022.05.014) (PMID:35688158)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was funded by a British Heart Foundation (BHF) CoRE award (RE/ 13/3/30183), Medical Research Scotland studentship (PhD-1049-2016), NC3R studentship (NC/P002196/1), BHF New Horizons grant (NH/14/2/ 31074), and a Medical Research Council UK award (MR/K013386/1).
• Keywords: repair, zebrafish, epicardium, vegf, notch, macrophages, heart, regeneration
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Taylor, Dr Jonathan
• Authors: Bruton, F. A., Kaveh, A., Ross-Stewart, K. M., Matrone, G., Oremek, M. E. M., Solomonidis, E. G., Tucker, C. S., Mullins, J. J., Lucas, C. D., Brittan, M., Taylor, J. M., Rossi, A. G., and Denvir, M. A.
• College/School: College of Science and Engineering > School of Physics and Astronomy
• Journal Name: Developmental Cell
• Publisher: Elsevier
• ISSN: 1534-5807
• ISSN (Online): 1878-1551
• Published Online: 09 June 2022
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in Developmental Cell 57(12): 1512-1528.e5
• Publisher Policy: Reproduced under a Creative Commons licence