Young enough hearts, soon after birth, are much more regenerative than adult hearts. Some species, such as zebrafish, never lose the youthful ability to regenerate damaged or lost sections of heart tissue. Mammals, however, all too quickly grow into an inferior regenerative capacity, most evident after injury to the nervous system or the heart. Is it possible to find the systems of molecular regulation that shut down very early in life, and at least temporarily and partially restore the ability to regenerate the heart without scarring, or to turn back heart failure? Finding the important parts of the complex network of genes and proteins that controls regeneration is a work in progress, and this open access paper covers some of what has been discovered to date. Answering the question of whether or not these discoveries can be used to safely enable regeneration, without risk of cancer or other issues, is similarly in progress. There have been interesting demonstrations in mice in the past few years, for example.
While a regenerative response is limited in the mammalian adult heart, it has been recently shown that the neonatal mammalian heart possesses a marked but transient capacity for regeneration after cardiac injury, including myocardial infarction. These findings evidence that the mammalian heart still retains a regenerative capacity and highlights the concept that the expression of distinct molecular switches (that activate or inhibit cellular mechanisms regulating tissue development and regeneration) vary during different stages of life, indicating that cardiac regeneration is an age-dependent process. Thus, understanding the mechanisms underpinning regeneration in the neonatal-infarcted heart is crucial to develop new treatments aimed at improving cardiovascular regeneration in the adult.
The present review summarizes the current knowledge on the pathways and factors that are known to determine cardiac regeneration in the neonatal-infarcted heart. In particular, we will focus on the effects of microRNA manipulation in regulating cardiomyocyte proliferation and regeneration, as well as on the role of the Hippo signaling pathway and Meis1 in the regenerative response of the neonatal-infarcted heart. We will also briefly comment on the role of macrophages in scar formation of the adult-infarcted heart or their contribution for scar-free regeneration of the neonatal mouse heart after myocardial infarction. Although additional research is needed in order to identify other factors that regulate cardiovascular regeneration, these pathways represent potential therapeutic targets for rejuvenation of aging hearts and for improving regeneration of the adult-infarcted heart.