Neonatal mouse hearts fully regenerate after ventricular resection similar to adult zebrafish. We established cryoinjury models to determine if different types and varying degrees of severity in cardiac injuries trigger different responses in neonatal mouse hearts. In contrast to ventricular resection, neonatal mouse hearts fail to regenerate and show severe impairment of cardiac function post transmural cryoinjury. However, neonatal hearts fully recover after non-transmural cryoinjury. Interestingly, cardiomyocyte proliferation does not significantly increase in neonatal mouse hearts after cryoinjuries. Epicardial activation and new coronary vessel formation occur after cryoinjury. The profibrotic marker PAI-1 is highly expressed after transmural but not non-transmural cryoinjuries, which may contribute to the differential scarring. Our results suggest that regenerative medicine strategies for heart injuries should vary depending on the nature of the injury.

The primordium that generates the embryonic posterior lateral line of zebrafish migrates from the head to the tip of the tail along a trail of SDF1-producing cells. This migration critically depends on the presence of the SDF1 receptor CXCR4 in the leading region of the primordium and on the presence of a second SDF1 receptor, CXCR7, in the trailing region of the primordium. Here we show that inactivation of the estrogen receptor ESR1 results in ectopic expression of cxcr4b throughout the primordium, whereas ESR1 overexpression results in a reciprocal reduction in the domain of cxcr4b expression, suggesting that ESR1 acts as a repressor of cxcr4b. This finding could explain why estrogens significantly decrease the metastatic ability of ESR-positive breast cancer cells. ESR1 inactivation also leads to extinction of cxcr7b expression in the trailing cells of the migrating primordium; this effect is indirect, however, and due to the down-regulation of cxcr7b by ectopic SDF1/CXCR4 signaling in the trailing region. Both ESR1 inactivation and overexpression result in aborted migration, confirming the importance of this receptor in the control of SDF1-dependent migration.

Opinion statement Myocardial infarction is the most common cause of cardiac injury in humans and results in acute loss of large numbers of myocardial cells. Unfortunately, the mammalian heart is unable to replenish the cells that are lost following a myocardial infarction and an eventual progression to heart failure can often occur as a result. Regenerative medicine based approaches are actively being developed; however, a complete blueprint on how mammalian hearts can regenerate is still missing. Knowledge gained from studying animal models, such as zebrafish, newt, and neonatal mice, that can naturally regenerate their hearts after injury have provided an understanding of the molecular mechanisms involved in heart repair and regeneration. This research offers novel strategies to overcome the limited regenerative response observed in human patients.