Mechanisms and Therapeutic Potential of Human Cardiomyocyte Proliferation

The limited capacity for cardiomyocyte proliferation in the adult human heart restricts its ability to recover from injury. Building on discoveries in regenerative model systems, such as zebrafish and neonatal mice, reactivation of a latent potential for cardiomyocyte proliferation is a strategy to promote therapeutic heart regeneration. Although cardiomyocyte proliferation remains modest even with the most effective mitogenic stimuli identified to date, evidence for a potential functional benefit in pre-clinical model systems has led to the initiation of several early-phase clinical programs. Here, we review insights from model organisms that inform the potential efficacy and limitations of therapeutic cardiomyocyte proliferation, systems to study human cardiomyocyte proliferation, and the natural history of cardiomyocyte proliferation in the human heart. We also examine the translational trajectory of selected discoveries, including therapeutic delivery modalities, and attendant safety concerns. Finally, we discuss critical challenges that will need to be addressed to enable successful clinical translation.