Abstract
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.
Highlights
British Heart Foundation and University of Edinburgh Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, United Kingdom
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
The present review summarizes the current knowledge on the pathways and factors that are known to determine cardiac regeneration in the neonatal-infarcted heart
Summary
Organ regeneration has been the focus of scientific research for over a century. For example, the ability of salamanders to regrow an entire lost limb after amputation has been studied for decades and their capacity to regenerate other damaged parts of their bodies is still of interest in the field of regenerative medicine. After surgical removal of about 20% of the ventricular myocardium of adult fish, the authors initially observed a rapid formation of a blood clot. This was replaced by a fibrin cap by 9 days post-resection. Over the 60 days, the fibrin cap was shown to regress as cardiomyocytes replaced the resected area, resulting in the complete regeneration of the myocardium. Using this resection model, the authors were able to show evidence of cardiomyocyte proliferation and suggested that cell proliferation was essential to scar-free regeneration of the adult zebrafish heart. Other studies using lineage tracing and electron microscopy techniques demonstrated that cardiomyocyte replenishment of the resected myocardium in the adult zebrafish occurred through existing cardiomyocyte de-differentiation and subsequent proliferation [15]
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