The transmembrane glycoprotein Gpnmb is required for the immune and fibrotic responses during zebrafish heart regeneration

Myocardial infarction occurs when coronary supply of oxygen and nutrients to part of the heart is interrupted. In contrast to adult mammals, adult zebrafish have a unique ability to regenerate their heart after cardiac injury. Several processes are involved in this regenerative response including inflammation, coronary endothelial cell proliferation and revascularization, endocardial expansion, cardiomyocyte repopulation, and transient scar formation. To identify potential regulators of zebrafish cardiac regeneration, we profiled the transcriptome of regenerating coronary endothelial cells at 7 days post cryoinjury (dpci) and observed the significant upregulation of dozens of genes including gpnmb. Gpnmb (glycoprotein non-metastatic melanoma protein B) is a transmembrane glycoprotein implicated in inflammation resolution and tissue regeneration. Transcriptomic profiling data of cryoinjured zebrafish hearts reveal that gpnmb is mostly expressed by macrophages. To investigate gpnmb function during zebrafish cardiac regeneration, we generated a full locus deletion (FLD) allele. We find that after cardiac cryoinjury, animals lacking gpnmb exhibit neutrophil retention and decreased macrophage recruitment as well as reduced myofibroblast numbers. Moreover, loss of gpnmb impairs coronary endothelial cell regeneration and cardiomyocyte dedifferentiation. Transcriptomic analyses of cryoinjured gpnmb mutant hearts identified enhanced collagen gene expression and the activation of extracellular matrix (ECM) related pathways. Furthermore, gpnmb mutant hearts exhibit larger fibrotic scars revealing additional defects in cardiac regeneration. Altogether, these data indicate that gpnmb expressing macrophages modulate inflammation and ECM deposition after cardiac cryoinjury in zebrafish and further highlight the importance of this subset of immune cells to support a regenerative response.