Gpnmb is required for immune and fibrotic responses during zebrafish heart regeneration

Myocardial infarction occurs when coronary supply of oxygen and nutrients to a part of the heart is interrupted. In contrast to adult humans, adult zebrafish have a unique ability to regenerate their heart after cardiac injury. To identify potential regulators of the regenerative response, we performed transcriptomics profiling of regenerating coronary endothelial cells (cECs) at 7 days post cryoinjury, when revascularization is vigorous, and identified gpnmb to be upregulated. Gpnmb (glycoprotein non-metastatic melanoma protein B) is a transmembrane glycoprotein implicated in inflammation resolution and tissue regeneration. Expression analyses at earlier time points revealed gpnmb specific expression in infiltrating macrophages post cryoinjury in zebrafish ventricles. Using newly generated gpnmb mutants, we analyze its role during heart regeneration and find that animals lacking gpnmb exhibit neutrophil retention and decreased macrophage recruitment as well as reduced myofibroblasts numbers. Moreover, loss of gpnmb impairs coronary endothelial cell regeneration and cardiomyocyte dedifferentiation. Transcriptomic analyses identified enhanced collagen production and extracellular matrix (ECM) related pathway activated in cryoinjured gpnmb mutant hearts. Furthermore, gpnmb mutant hearts exhibit larger fibrotic scars revealing defects in cardiac regeneration. Overall, these data suggest that gpnmb expressing macrophages modulate inflammation and ECM deposition after cardiac cryoinjury and highlight the importance of this subset of immune cells to support a regenerative response. To investigate the role of gpnmb during zebrafish heart regeneration, we generated gpnmb mutants and performed comparative RNAseq analysis on WT and MUT