Unknown,Transcriptomics,Genomics,Proteomics

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MicroRNA expression profiling of zebrafish heart regeneration

ABSTRACT: Cardiovascular disease is the leading cause of morbidity and mortality in the Western world due to a limited regenerative capacity. In lieu of new muscle synthesis, the human heart replaces necrotic tissue with deposition of a non-contractile scar. In contrast, the adult zebrafish is endowed with a remarkable regenerative capacity, capable of de novo cardiomyocyte (CM) creation and scar tissue resolution when challenged with an acute injury. In these studies, we examined the contributions of the dynamically regulated microRNA, miR-101a, during adult zebrafish heart regeneration. We demonstrate that miR-101a expression is rapidly depleted within 3 days post-amputation (dpa) but is highly upregulated by 7-14 dpa, before returning to uninjured levels at the completion of the regenerative process. Employing heat-inducible transgenic strains and antisense oligonucleotides, we demonstrate that decreases in miR-101a levels at the onset of cardiac injury enhanced CM proliferation. Interestingly, prolonged suppression of miR-101a activity stimulates new muscle synthesis but with defects in scar tissue resolution. Upregulation of miR-101a expression between 7-14 dpa is critical to stimulate remodeling of the scar. Through a series of studies, we identified the proto-oncogene, fosab (cfos) as a potent miR-101a target gene, stimulator of CM proliferation, and inhibitor of scar tissue remodeling. Importantly, combinatorial depletion of fosab and miR-101a activity rescued defects in scar tissue resolution mediated by miR-101a inhibition alone. In summation, our studies indicate that the precise temporal modulation in the miR-101a/fosab genetic axis is critical for coordinating CM proliferation and scar tissue resolution during zebrafish heart regeneration. Pooled cardiac samples from uninjured and regenerating (6hpa) adult fish in biological triplicate.

ORGANISM(S): Danio rerio

SUBMITTER: Benjamin King

PROVIDER: E-GEOD-74494 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: There is a limited capacity to repair damage in the mammalian heart after birth, which is primarily due to the inability of cardiomyocytes to proliferate after birth. This is in contrast to zebrafish and salamander, in which cardiomyocytes retain the ability to proliferate throughout life and can regenerate their heart after significant damage. Recent studies in zebrafish and rodents implicate microRNAs (miRNAs) in the regulation of genes responsible for cardiac cell cycle progression and regeneration, in particular, miR-133a, the miR-15 family, miR-199a and miR-590. However, the significance of these miRNAs and miRNA in general in the regulation of cardiomyocyte proliferation in large mammals, including humans, where the timing of heart development relative to birth is very different than in rodents, is unclear. To determine the involvement of miRNAs in the down-regulation of cardiomyocyte proliferation occurring before birth in large mammals, we investigated miRNA and target gene expression in sheep hearts before and after birth. The experimental approach included targeted transcriptional profiling of miRNA and target mRNA previously identified in rodent studies as well as genome-wide miRNA profiling using microarrays. Results: The cardiac expression of miR-133a increased and its target gene IGF1R decreased with increasing age, reaching their respective maximum and minimum abundance when the majority of ovine cardiomyocytes were quiescent. The expression of the miR-15 family members was variable with age, however, four of their target genes decreased with age. These latter profiles are inconsistent with the direct involvement of this family of miRNA in cardiomyocyte quiescence in late gestation sheep. The expression patterns of ‘pro-proliferative’ miR-199a and miR-590 were also inconsistent with their involvement in cardiomyocyte quiescence. Consequently, miRNA microarray analysis was undertaken, which identified six discrete clusters of miRNA with characteristic developmental profiles. The functions of predicted target genes for the miRNA in four of the six clusters were enriched for aspects of cell division and regulation of cell proliferation suggesting a potential role of these miRNA in regulating cardiomyocyte proliferation. Conclusion: The results of this study show that the expression of miR-133a and one of its target genes is consistent with it being involved in the suppression of cardiomyocyte proliferation, which occurs across the last third of gestation in sheep. The expression patterns of the miR-15 family, miR-199a and miR-590 were inconsistent with direct involvement in the regulation cardiomyocyte proliferation in sheep, despite studies in rodents demonstrating that their manipulation can influence the degree of cardiomyocyte proliferation. miRNA microarray analysis suggests a coordinated and potentially more complex role of multiple miRNA in the regulation of cardiomyocyte quiescence and highlights significant differences between species that may reflect their substantial differences in the timing of this developmental process. RNA, (2 µg) from three heart samples from each of the 91 d (fetus), 141 d (fetus), 5 d (postnatal) and 173 d (postnatal) groups, was used for analysis according to standard procedures. The experimental design included three biological replicates from each of the four normal developmental ages in sheep and thus a total of 12 samples was analyzed.

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.

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MicroRNA expression profiling of zebrafish heart regeneration

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