Regulation of endogenous cardiomyocyte proliferation: The known unknowns

Myocardial regeneration in patients with cardiac damage is a long-sought goal of clinical medicine. In animal species in which regeneration occurs spontaneously, as well as in neonatal mammals, regeneration occurs through the proliferation of differentiated cardiomyocytes, which re-enter the cell cycle and proliferate. Hence, the reprogramming of the replicative potential of cardiomyocytes is an achievable goal, provided that the mechanisms that regulate this process are understood. Cardiomyocyte proliferation is under the control of a series of signal transduction pathways that connect extracellular cues to the activation of specific gene transcriptional programmes, eventually leading to the activation of the cell cycle. Both coding and non-coding RNAs (in particular, microRNAs) are involved in this regulation. The available information can be exploited for therapeutic purposes, provided that a series of conceptual and technical barriers are overcome. A major obstacle remains the delivery of pro-regenerative factors specifically to the heart. Improvements in the design of AAV vectors to enhance their cardiotropism and efficacy or, alternatively, the development of non-viral methods for nucleic acid delivery in cardiomyocytes are among the challenges ahead to progress cardiac regenerative therapies towards clinical application.