Mechanisms of Cardiac Regeneration

Abstract

Adult humans fail to regenerate their hearts following injury, and this failure to regenerate myocardium is a leading cause of heart failure and death worldwide. Although all adult mammals appear to lack significant cardiac regeneration potential, some vertebrates can regenerate myocardium throughout life. In addition, new studies indicate that mammals have cardiac regeneration potential during development and very soon after birth. The mechanisms of heart regeneration among model organisms, including neonatal mice, appear remarkably similar. Orchestrated waves of inflammation, matrix deposition and remodeling, and cardiomyocyte proliferation are commonly seen in heart regeneration models. Understanding why adult mammals develop extensive scarring instead of regeneration is a crucial goal for regenerative biology.

Figure 1. Cardiac Regeneration Across Model Organisms

Cardiac regeneration has been studied in a number of model systems. While lower vertebrate model species like teleost fish and urodeles retain regenerative capacity throughout adult life, anurans and mammals lose this ability in adulthood. It should be noted that not all teleost fish have been reported to have complete regenerative response upon heart injury. Future studies on different species and different injury types will broaden our understanding of evolutionary conservation of capacity for cardiac regeneration.

Figure 2. Mammalian response to injury

Cardiac regeneration has been explored in fetal, neonatal and adult mammals and occurs to a different extent in each model. At embryonic stages, compensatory growth in cardiomyocytes restores up to 50% of lost tissue. In the neonatal mouse, tissue can replace a majority of lost cardiomyocytes with minimal scarring in myocardial infarction and ventricular resection models. In the adult mouse, cardiomyocyte proliferation is insufficient to replace lost tissue, and extracellular matrix deposition following injury leads to extensive scarring.

Figure 3. Evolutionarily conserved mechanisms of cardiac regeneration

Cardiomyocyte proliferation is central to the process of cardiac regeneration, and several processes have been shown to modulate proliferation upon injury in a range of organisms that are capable of a complete regenerative response. An inflammatory response tightly regulates a fine balance between proliferation and repair. Extracellular matrix deposition following injury creates a permissive environment for cellular proliferation and is influenced by signals from the epicardium following injury. Neoangiogenesis is triggered by FGF and PDGF signaling and provides a supply of oxygen and nutrients to the regrowing tissue, and new studies emphasize the requirement of nerves in the regenerate.