PUBLICATION
Macrophages trigger cardiomyocyte proliferation by increasing epicardial vegfaa expression during larval zebrafish heart regeneration
- 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., Denvir, M.A.
- ID
- ZDB-PUB-220611-16
- Date
- 2022
- Source
- Developmental Cell 57(12): 1512-1528.e5 (Journal)
- Registered Authors
- Lucas, Chris, Mullins, John, Rossi, Adriano
- Keywords
- epicardium, heart, macrophages, notch, regeneration, repair, vegf, zebrafish
- MeSH Terms
-
- Animals
- Cell Proliferation
- Heart/physiology
- Larva/metabolism
- Macrophages/metabolism
- Mammals/metabolism
- Myocytes, Cardiac*/metabolism
- Zebrafish*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 35688158 Full text @ Dev. Cell
Citation
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., Denvir, M.A. (2022) Macrophages trigger cardiomyocyte proliferation by increasing epicardial vegfaa expression during larval zebrafish heart regeneration. Developmental Cell. 57(12):1512-1528.e5.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping