Cellular drivers of injury response and regeneration in the adult zebrafish heart

Myocardial infarction is a leading cause of death worldwide, as the adult human heart does not have the ability to regenerate efficiently after insults. In contrast, the adult zebrafish heart has a high capacity for regeneration, and understanding the mechanisms of regenerative processes in fish allows identification of novel therapeutic strategies. While several pro-regenerative factors have been described, the cell types orchestrating heart regeneration remain largely elusive. To overcome this conceptual limitation, we dissected cell type diversity in the regenerating zebrafish heart based on single cell transcriptomics and spatiotemporal analysis. We discovered a dramatic induction of several pro-regenerative cell types with fibroblast characteristics. To understand the cascade of events leading to heart regeneration, we determined the origin of these cell types by high-throughput lineage tracing. We found that pro-regenerative fibroblasts are derived from two separate sources, the epicardium and the endocardium. Mechanistically, we identified Wnt signaling as a key regulator of the endocardial regenerative response. In summary, our results uncover specialized fibroblast cell types as major drivers of heart regeneration, thereby opening up new possibilities to interfere with the regenerative capacity of the vertebrate heart.