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Comparative transcriptome profiling of zebrafish and medaka hearts following cardiac cryoinjury

ABSTRACT: Comparative transcriptome profiling of zebrafish and medaka hearts following cardiac cryoinjury

OTHER RELATED OMICS DATASETS IN: GSE94617

PROVIDER: PRJNA371613 | ENA |

REPOSITORIES: ENA

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Project description:Heart failure results from the inability of the human heart to replenish damaged tissue after myocardial infarction (MI), forming an unresolved scar which leads to functional impairment and tissue remodeling. Unlike humans, many animals, including certain fish and amphibians, are able to regenerate their hearts. Comparative analyses have been performed in many model systems including zebrafish (Danio rerio), with the goal to identify factors that could promote cardiac regeneration in humans. However, profound physiological differences between regenerative and non-regenerative models often make it difficult to extract informative data that are directly relevant to cardiac regeneration. Recently, medaka (Oryzias latipes), another fresh water teleost, has been reported to lack activation of neovascularization and cardiomyocyte (CM) proliferation post cardiac injury, and to display excessive fibrosis and an unresolved scar. This finding constitutes a unique opportunity to directly compare reparative responses to cardiac injury between regenerative (zebrafish) and non-regenerative (medaka) models with common physiological condition and anatomical structures, as well as phylogenetically close orthologous genes. Here we investigate potential triggers that promote heart regeneration using a comparative transcriptomic analysis between zebrafish and medaka. We generated a detailed dataset containing more than 15000 orthologous genes, covering multiple time points in the first week after cardiac injury. Analyses based on gene ontology revealed that differential responses in processes such as the immune response and angiogenesis exist between the two models. Pathway analyses further suggested potential candidates accounting for these differential responses including the Toll-like receptor agonist poly I:C. Altogether, these data provide further insight into the complex role of the immune response during regeneration, and serve as a platform to identify and test additional regulators of cardiac repair.

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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Comparative transcriptome profiling of zebrafish and medaka hearts following cardiac cryoinjury

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