Comparison of cardiac regeneration capacity between zebrafish and medaka reveals a regenerative response in both teleost species

Danio rerio (zebrafish) can regenerate their heart upon loss of over 20% of the total myocardium. A second teleost species, Oryzias latipes (medaka), however, has been described to lack this capacity and respond to a lesion forming a permanent fibrotic scar after heart resection. An altered immune response has been suggested to underlie the differences in heart regeneration. However, a thorough comparative analysis between zebrafish and medaka through the different steps of regeneration was lacking. Here, we provide an in-depth characterization of the injury response and heart regeneration in both teleost species (AB and Cab strains, respectively) after ventricular cryoinjury (CI). We observed an exacerbated neutrophil activation with little evidence of macrophage recruitment in medaka compared to zebrafish. However, cardiomyocyte proliferation significantly increased in both teleosts upon CI. We also observed transient blood vessel formation in medaka and a significant reduction of fibrotic tissue at 30 and 60 dpi compared to 7 dpi. However, some animals presented signs of an irreversible scar at 60 dpi and ventricular indentations suggestive of impaired regeneration. Nonetheless, echocardiographic assessment revealed cardiac function recovery in a subset of medaka, independent of the fibrotic tissue resolution. Overall, we conclude that the cardiac regenerative ability is broader in medaka than anticipated.