Evolution, comparative biology and ontogeny of vertebrate heart regeneration

Abstract

There are 64,000 living species of vertebrates on our planet and all of them have a heart. Comparative analyses devoted to understanding the regenerative potential of the myocardium have been performed in a dozen vertebrate species with the aim of developing regenerative therapies for human heart disease. Based on this relatively small selection of animal models, important insights into the evolutionary conservation of regenerative mechanisms have been gained. In this review, we survey cardiac regeneration studies in diverse species to provide an evolutionary context for the lack of regenerative capacity in the adult mammalian heart. Our analyses highlight the importance of cardiac adaptations that have occurred over hundreds of millions of years during the transition from aquatic to terrestrial life, as well as during the transition from the womb to an oxygen-rich environment at birth. We also discuss the evolution and ontogeny of cardiac morphological, physiological and metabolic adaptations in the context of heart regeneration. Taken together, our findings suggest that cardiac regenerative potential correlates with a low-metabolic state, the inability to regulate body temperature, low heart pressure, hypoxia, immature cardiomyocyte structure and an immature immune system. A more complete understanding of the evolutionary context and developmental mechanisms governing cardiac regenerative capacity would provide stronger scientific foundations for the translation of cardiac regeneration therapies into the clinic.

Figure 1

Heart regenerative capacity in warm- or cold-blooded animals. For each species, cardiac regenerative ability is indicated in green (ability to regenerate), orange (incomplete capacity to regenerate) or red (incapacity to regenerate). In each case, the approach used to induce cardiac damage and the references associated are indicated. In warm-blooded species, cardiac regeneration appears to be restricted to a defined early-developmental period during embryonic and early-neonatal life. In cold-blooded animals, six out of nine species have the ability to regenerate their heart during adult life, whereas three out of nine species show an incomplete capacity or incapacity to undergo heart regeneration.

Figure 2

Different approaches used to study cardiac regeneration in vertebrates. The four main methodological approaches used in the literature to induce cardiac damage are indicated. For each approach, the type of injury induced, the extent of tissue removal and the extent of inflammation and ECM deposition after injury are indicated. The ability to regenerate the myocardium after the defined type of injury is indicated for the vertebrate species analysed. NTC, non-transmural cryoinjury; TC, transmural cryoinjury.

Figure 3

Evolution of heart regenerative capacity, heart morphology and physiology. On the evolutionary tree species in green have the capacity to regenerate the damaged myocardium, species in red have a transient regenerative ability, which is lost during adult life, and species in orange have an incomplete cardiac regenerative ability. In the table data are provided for zebrafish, axolotl or mouse models. The first column describes heart morphology, the second column indicates the presence or absence of a coronary vasculature, the third column indicates the structural maturity and nucleation status of cardiomyocytes and the fourth column indicates the capacity for thermoregulation, as well as the environmental temperature (for zebrafish and axolotl) or body temperature (for neonatal or adult mice) and heart pressure. A, atrium; V, ventricle.

Figure 4

Cardiomyocyte metabolism and heart regeneration. Organisms in red are unable to regenerate the heart after cardiac damage, their energy demand is high and they mainly use oxidative phosphorylation (OXPHOS) to produce ATP. OXPHOS induces the generation of reactive oxygen species (ROS), which have been implicated in DNA damage and cell-cycle arrest. Organisms that have a low-energy demand and use anaerobic glycolysis as their main source of ATP production are shown in green.