Extra- and intracellular factors regulating cardiomyocyte proliferation in postnatal life.

One of the striking differences that distinguish the adult from the embryonic heart in mammals and set it apart from the heart in urodeles and teleosts is the incapacity of cardiomyocytes to respond to damage by proliferation. While the molecular reasons underlying these characteristics still await elucidation, mounting evidence collected over the last several years indicates that cardiomyocyte proliferation can be modulated by different extracellular molecules. The exogenous administration of selected growth factors is capable of inducing neonatal and, in some instances, also adult cardiomyocyte proliferation. Other diffusible factors can regulate the proliferation and cardiac commitment of endogenous or implanted stem cells. While the individual role of these factors in the paracrine control of normal heart homeostasis still needs to be defined, this information is relevant for the development of novel therapeutic strategies for cardiac regeneration. In addition, recent evidence indicates that postnatal cardiomyocyte proliferation is controlled by genetically defined pathways, such as the Hippo pathway, and can be modulated by perturbing the endogenous cardiomyocyte microRNA network; the identification of the cytokines that activate these molecular circuits holds great potential for clinical translation.