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

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE270188 | GEO | 2025/08/03

REPOSITORIES: GEO

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Project description:To determine whether lymphangiogenesis is required for cardiac regeneration, vegfc(hy-/-);vegfd(-/-) double mutants and control hearts were collected and analyzed at 180 days after cryoinjury, this corresponds to a time point when the regenerative response is normally completed in wild-type zebrafish. Surprisingly, the vast majority (~70%) of vegfc(hy-/-);vegfd(-/-) mutants, which completely lack cardiac lymphatics, were able to mount a complete regenerative response without any signs of fibrosis. We found that the cardiac regenerative response was impaired only in a subset (3/8) of vegfc(hy-/-);vegfd(-/-) mutants, which were characterized by large deposits of fibrotic scar tissue present at the injury site. To profile vegfc/d-dependent genetic pathways contributing to lymphangiogenesis in cardiac regeneration, we performed RNA-seq on cryosections from control and mutant ventricles at 180 days following cryoinjury. Overall, vegfc(hy-/-);vegfd(-/-) mutant ventricles were characterized by an up-regulation of pathways related to metabolism, inflammation, hemostasis, negative regulation of FGFR signaling, translation, protein maturation and nonsense mediated decay compared to control hearts. These findings are consistent with the cardiac hypertrophy phenotype in vegfc(hy-/-);vegfd(-/-) mutants. To determine the molecular basis of the regenerative capacity within the mutant fish population, we next compared the transcriptional profiles of vegfc(hy-/-);vegfd(-/-) mutant hearts that did not regenerate (n=3) with the profiles of mutant hearts which recovered completely (n=5) at 180 days post cryoinjury. The subset of vegfc(hy-/-);vegfd(-/-) mutant hearts that failed to regenerate were characterized by an enrichment of inflammatory pathways, in particular TRAF6-mediated IRF7 activation, interferon alpha beta signaling and regulation of IFNA signaling. These findings suggest that loss of the vegfc/d signaling axis causes a sustained and pronounced inflammatory response following injury. This change in the cardiac micro-environment seems to favor adverse conditions which impair the regenerative process.

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

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