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[This retracts the article DOI: 10.1016/j.isci.2019.06.017.].
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[This retracts the article DOI: 10.1016/j.isci.2019.04.009.].
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The adult zebrafish is capable of regenerating heart muscle, resolving collagen tissue, and fully restoring heart function throughout its life. In this study, we show that the highly upregulated, epicardium-enriched microRNA let-7i functions in wound closure and cardiomyocyte proliferation. RNA sequencing experiments identified upregulated expression of members of the tumor necrosis factor (TNF) signaling pathway in the absence of let-7. Importantly, co-suppression of TNF and let-7 activity rescued epicardium migration and cardiomyocyte proliferation defects induced by depletion of let-7 alone. Sensitizing animals to low levels of TNF activity before injury culminated in repressed cardiomyocyte proliferation and wound closure defects, suggesting that levels of inflammation at the onset of injury are critical for heart regeneration. Our studies indicate that injury-induced reduction in TNF signaling by let-7 in the epicardium creates a pro-regenerative environment for cardiomyocyte proliferation during adult heart regeneration.
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Regeneration is an endogenous process of tissue repair that culminates in complete restoration of tissue and organ function. While regenerative capacity in mammals is limited to select tissues, lower vertebrates like zebrafish and salamanders are endowed with the capacity to regenerate entire limbs and most adult tissues, including heart muscle. Numerous profiling studies have been conducted using these research models in an effort to identify the genetic circuits that accompany tissue regeneration. Most of these studies, however, are confined to an individual injury model and/or research organism and focused primarily on protein encoding transcripts. Here we describe RegenDbase, a new database with the functionality to compare and contrast gene regulatory pathways within and across tissues and research models. RegenDbase combines pipelines that integrate analysis of noncoding RNAs in combination with protein encoding transcripts. We created RegenDbase with a newly generated comprehensive dataset for adult zebrafish heart regeneration combined with existing microarray and RNA-sequencing studies on multiple injured tissues. In this current release, we detail microRNA-mRNA regulatory circuits and the biological processes these interactions control during the early stages of heart regeneration. Moreover, we identify known and putative novel lncRNAs and identify their potential target genes based on proximity searches. We postulate that these candidate factors underscore robust regenerative capacity in lower vertebrates. RegenDbase provides a systems-level analysis of tissue regeneration genetic circuits across injury and animal models and addresses the growing need to understand how noncoding RNAs influence these changes in gene expression.