Cardiomyocyte autophagy promotes a pro-regenerative immune response during cardiac regeneration

Adult zebrafish possess a remarkable ability to regenerate their heart following cardiac injury. Over the past decades, our understanding of the diverse cell types involved in zebrafish cardiac regeneration has greatly advanced. However, the mechanisms governing their interaction and how heterocellular crosstalk drives regeneration remain poorly understood. Here, we identify cardiomyocyte autophagy as a key link between the cardiomyocyte injury response and heterocellular crosstalk between cardiomyocytes and macrophages. We find that cardiomyocyte autophagy is downstream of AP-1 transcription factors. Using newly generated genetic tools, we find that cardiomyocyte autophagy is an important regulator of cardiomyocyte protrusion into the fibrotic injured tissue and its disruption leads to defects in scar resolution. Notably, we find that blocking cardiomyocyte autophagy has a marked effect on the transcriptomic signatures in cardiac macrophages, shifting gene expression from phagocytic/pro-inflammatory/pro-reparative towards pro-angiogenic and pro-fibrotic states. Altogether, our results uncover autophagy as a mechanism linking cardiomyocyte injury responses to macrophage phenotype and coordinated tissue remodeling during heart regeneration.