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In vivo RNA metabolic labeling identifies the sentinel cells of the regenerating zebrafish heart [scslam-seq]

ABSTRACT: The adult zebrafish heart has high regenerative capacity. Heart injury triggers a cascade of events including inflammation, fibrosis, revascularization, and proliferation of cardiomyocytes, culminating in full functional recovery of the heart. However, the first events that are induced upon injury and trigger the regenerative cascade remain elusive. Here, we established in vivo single-cell RNA metabolic labeling in the adult heart to systematically identify the cells that first respond to injury, as well as the processes that are induced in these sentinel cells. We found that activation of damage response pathways including Toll-like receptor signaling and expression of pro-inflammatory genes in macrophages are the first response to heart injury. In conjunction with detailed dissection of single-cell transcriptomics atlases, this finding led us to postulate that macrophage-specific inhibition of Toll-like receptor signaling would improve hallmarks of regeneration, a hypothesis we validated in functional experiments. In summary, our work establishes RNA metabolic labeling as a powerful approach for measuring perturbation response in vivo, identifies macrophages as the sentinel cells of the heart, and highlights the importance of fine-tuning the early pro-inflammatory phase for optimal regenerative outcomes.

ORGANISM(S): Danio rerio

PROVIDER: GSE305095 | GEO | 2026/03/30

REPOSITORIES: GEO

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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.

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In vivo RNA metabolic labeling identifies the sentinel cells of the regenerating zebrafish heart [scslam-seq]

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