Zebrafish heart regeneration occurs through the proliferation of differentiated cardiomyocytes rather than stem/progenitor cells. Using a Cre/lox genetic lineage-tracing system, researchers showed that newly formed cardiomyocytes in regenerating zebrafish hearts are derived from pre-existing differentiated cardiomyocytes. These cells undergo limited dedifferentiation, characterized by sarcomeric disassembly, detachment from one another, and expression of cell cycle regulators. Polo-like kinase 1 (plk1) is essential for cardiomyocyte proliferation during regeneration. Inhibition of plk1 significantly reduced heart regeneration, indicating its critical role. Electron microscopy revealed that cardiomyocytes in regenerating hearts show structural changes, including loss of sarcomeric organization and intercellular spaces, but remain healthy. These findings suggest that zebrafish heart regeneration is primarily driven by pre-existing cardiomyocytes, with limited dedifferentiation facilitating cell cycle re-entry. The study also highlights the importance of plk1 and mps1 in the regenerative process. These results provide insights into the mechanisms of heart regeneration and suggest that similar processes might be applicable to mammals.Zebrafish heart regeneration occurs through the proliferation of differentiated cardiomyocytes rather than stem/progenitor cells. Using a Cre/lox genetic lineage-tracing system, researchers showed that newly formed cardiomyocytes in regenerating zebrafish hearts are derived from pre-existing differentiated cardiomyocytes. These cells undergo limited dedifferentiation, characterized by sarcomeric disassembly, detachment from one another, and expression of cell cycle regulators. Polo-like kinase 1 (plk1) is essential for cardiomyocyte proliferation during regeneration. Inhibition of plk1 significantly reduced heart regeneration, indicating its critical role. Electron microscopy revealed that cardiomyocytes in regenerating hearts show structural changes, including loss of sarcomeric organization and intercellular spaces, but remain healthy. These findings suggest that zebrafish heart regeneration is primarily driven by pre-existing cardiomyocytes, with limited dedifferentiation facilitating cell cycle re-entry. The study also highlights the importance of plk1 and mps1 in the regenerative process. These results provide insights into the mechanisms of heart regeneration and suggest that similar processes might be applicable to mammals.