The adult zebrafish heart can regenerate after injury, but the earliest gene expression changes that trigger this process remain poorly understood. Here we show that in vivo single-cell RNA metabolic labeling, which marks newly made RNA in individual cells, can capture rapid responses in the adult zebrafish heart after injury. Within the first 6 h, we detect activation of innate immune programs, including Toll-like receptor signaling, in a subset of macrophage-like immune cells. Analysis of a larger single-cell dataset indicates that neutrophils also contribute to this early response. Guided by these data, we show that macrophage-specific inhibition of the Toll-like receptor adaptor MyD88 reduces the pro-inflammatory macrophage response at the injury site and improves early hallmarks of regeneration. Our work establishes RNA metabolic labeling as a useful approach for measuring acute responses in vivo at single-cell resolution and identifies early immune-cell activation as a tunable component of heart regeneration.
Institut(e)Institute of Pancreatic Islet Research (IPI)
FörderungenU.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD) Deutsche Forschungsgemeinschaft (German Research Foundation) Studienstiftung des Deutschen Volkes (German National Academic Foundation) European Molecular Biology Organization (EMBO) TAIWAN (NSTC) - LITHUANIA (LMT) joint research grant (NSTC 113-2923-B-001-003-MY2) EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (200 Helmholtz Association Deutsches Zentrum fr Herz-Kreislaufforschung (Deutsches Zentrum fr Herz-Kreislaufforschung e.V.) Fondation Leducq