In vivo single-cell RNA metabolic labeling resolves early transcriptional responders in the regenerating zebrafish heart [scrna-seq]

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.