Cardiomyocyte Proliferation as a Source of New Myocyte Development in the Adult Heart

Abstract

Cardiac diseases such as myocardial infarction (MI) can lead to adverse remodeling and impaired contractility of the heart due to widespread cardiomyocyte death in the damaged area. Current therapies focus on improving heart contractility and minimizing fibrosis with modest cardiac regeneration, but MI patients can still progress to heart failure (HF). There is a dire need for clinical therapies that can replace the lost myocardium, specifically by the induction of new myocyte formation from pre-existing cardiomyocytes. Many studies have shown terminally differentiated myocytes can re-enter the cell cycle and divide through manipulations of the cardiomyocyte cell cycle, signaling pathways, endogenous genes, and environmental factors. However, these approaches result in minimal myocyte renewal or cardiomegaly due to hyperactivation of cardiomyocyte proliferation. Finding the optimal treatment that will replenish cardiomyocyte numbers without causing tumorigenesis is a major challenge in the field. Another controversy is the inability to clearly define cardiomyocyte division versus myocyte DNA synthesis due to limited methods. In this review, we discuss several studies that induced cardiomyocyte cell cycle re-entry after cardiac injury, highlight whether cardiomyocytes completed cytokinesis, and address both limitations and methodological advances made to identify new myocyte formation.

Keywords: cardiac regeneration; cardiomyocyte cytokinesis; cardiomyocyte proliferation; myocardial infarction.

Figure 1

Regulators of the cardiomyocyte cell cycle. Summary of signaling pathways, cell cycle genes, and extracellular stimuli that induce cardiomyocyte proliferation, as discussed in this review. This includes cell cycle promotors and inhibitors, both the hippo and neuregulin pathways, microRNAs, and metabolic regulators, such as hypoxia and PDK4. Cyclins and cyclin-dependent kinases promote cell cycle activation and progression, while cyclin-dependent kinase inhibitors such as p21, p27, and p57 inhibit the cell cycle. In the hippo pathway, activation of upstream kinases (Mst1/2, Sav1, Mob1/2, and Lats1/2) phosphorylate the downstream transcription co-activators (YAP/TAZ) to promote their degradation. However, inactivation of upstream kinases causes YAP/TAZ to translocate to the nucleus to promote cell cycle re-entry in cardiomyocytes. Neuregulin (NRG1) binds to its tyrosine receptor subunits (ERBB2 and ERBB4) to activate a downstream signaling pathway (PI3K/AKT) and induce myocyte proliferation. Several microRNAs (miRNAs) also regulate the cell cycle to influence new myocyte formation. Hypoxia and PDK4 lead to a metabolic switch in cardiomyocytes from mitochondrial oxidative phosphorylation to anaerobic glycolysis for energy production. This metabolic change influences cell cycle activation in cardiomyocytes. PDK4, pyruvate dehydrogenase kinase 4.

Figure 2

Systemic hypoxia can induce cardiomyocyte proliferation and cardiac regeneration. Healthy adult hearts have normal cardiac function, blood flow, and utilize oxidative phosphorylation to generate energy. Following myocardial infarction (MI), there is increased cardiomyocyte hypertrophy, scar formation, reduced cardiac pump function, and minimal cardiomyocyte proliferation. These adverse changes can progress and lead to heart failure overtime with increased dilation of the myocardium, poor blood circulation, and declined cardiac function. However, a recent study in mice [51] demonstrated that systemic hypoxemia post MI caused cardiomyocytes to undergo a metabolic switch from oxidative phosphorylation to anaerobic glycolysis. Hypoxia also enhanced cardiomyocyte proliferation and hypoxic myocytes resembled fetal cardiomyocytes. Hypoxic mice had increased angiogenesis, reduced scar size, and improved cardiac function. When the mice returned to normoxia, cardiac repair and elevated cardiac pump function was sustained.