Heart regeneration and the cardiomyocyte cell cycle

Abstract

Cardiovascular disease and in particular, heart failure are still main causes of death; therefore, novel therapeutic approaches are urgently needed. Loss of contractile substrate in the heart and limited regenerative capacity of cardiomyocytes are mainly responsible for the poor cardiovascular outcome. This is related to the postmitotic state of differentiated cardiomyocytes, which is partly due to their polyploid nature caused by cell cycle variants. As such, the cardiomyocyte cell cycle is a key player, and its manipulation could be a promising strategy for enhancing the plasticity of the heart by inducing cardiomyocyte proliferation. This review focuses on the cardiac cell cycle and its variants during postnatal growth, the different regenerative responses of the heart in dependance of the developmental stage and on manipulations of the cell cycle. Because a therapeutic goal is to induce authentic cell division in cardiomyocytes, recent experimental approaches following this strategy are also discussed.

Keywords: Cardiomyocyte; Cell growth; Heart; Regeneration; Transgenic animal models.

Fig. 1

The cell cycle in cardiac regeneration. Cardiac plasticity after injury depends on the developmental stage (e.g., embryonic, neonatal, or adult). Embryonic lesions regenerate by CM division (structure and cell number restored). Lesions in neonatal hearts cause CM cell cycle entry and hyperplasia leading to compensatory growth, as the original structure is not fully restored. It is unclear if endoreduplication or binucleation plays a role in the response. After lesions in adult hearts, neither structure nor cell numbers are restored. CMs enter the cell cycle and undergo endoreduplication leading to hypertrophy