Model organisms at the heart of regeneration

Abstract

Heart failure is a major cause of death worldwide owing to the inability of the adult human heart to regenerate after a heart attack. However, many vertebrate species are capable of complete cardiac regeneration following injury. In this Review, we discuss the various model organisms of cardiac regeneration, and outline what they have taught us thus far about the cellular and molecular responses essential for optimal cardiac repair. We compare across different species, highlighting evolutionarily conserved mechanisms of regeneration and demonstrating the importance of developmental gene expression programmes, plasticity of the heart and the pathophysiological environment for the regenerative response. Additionally, we discuss how the findings from these studies have led to improvements in cardiac repair in preclinical models such as adult mice and pigs, and discuss the potential to translate these findings into therapeutic approaches for human patients following myocardial infarction.

Keywords: Cardiac regeneration; Cardiac repair; Cardiomyocytes; Myocardial infarction; Regenerative medicine.

Fig. 1.

Animal models of cardiac regeneration. Phylogenetic tree to demonstrate the evolutionary divergence of the different vertebrate species used in the study of cardiac regeneration.

Fig. 2.

Methods of cardiac injury in the zebrafish. (A) Apical resection involves surgical removal of ∼20% of the ventricular apex. (B) In the cryoinjury model, ∼25% of the ventricle is damaged by placing a cryoprobe onto the heart. (C) Genetic ablation leads to the loss of ∼60% of cardiomyocytes.

Fig. 3.

Cardiac regeneration in zebrafish. Following cardiac injury, diploid cardiomyocytes undergo dedifferentiation and proliferate to replace the damaged tissue. Signals from the activated epicardium and endocardium, such as retinoic acid (RA) and vascular endothelial growth factor Aa (Vegfaa), stimulate such proliferation, whilst epicardial fibroblast growth factor (FGF) signalling induces neovascularisation to restore blood flow.

Fig. 4.

Mouse models of neonatal cardiac regeneration. Following a thoracotomy, the heart is exposed from the chest and can be injured by either: (A) removal of the ventricular apex; (B) ligation of the left anterior descending coronary artery (LAD) using a suture; or (C) a cryoprobe held against the ventricle wall.

Fig. 5.

Loss of cardiac regeneration potential in neonatal mice. Within the first week of life, the neonatal mouse loses the ability to regenerate its heart. This diagram highlights some of the key changes that occur within the first week of life that contribute to the loss of regenerative capacity. CM, cardiomyocyte; ROS, reactive oxygen species.