Abstract
The adult mammalian heart is incapable of regeneration following cardiac injury, leading to a decline in function and eventually heart failure. One of the most evident barriers limiting cardiac regeneration is the inability of cardiomyocytes to divide. It has recently become clear that the mammalian heart undergoes limited cardiomyocyte self-renewal throughout life and is even capable of modest regeneration early after birth. These exciting findings have awakened the goal to promote cardiomyogenesis of the human heart to repair cardiac injury or treat heart failure. We are still far from understanding why adult mammalian cardiomyocytes possess only a limited capacity to proliferate. Identifying the key regulators may help to progress towards such revolutionary therapy. Specific noncoding RNAs control cardiomyocyte division, including well explored microRNAs and more recently emerged long noncoding RNAs. Elucidating their function and molecular mechanisms during cardiomyogenesis is a prerequisite to advance towards therapeutic options for cardiac regeneration. In this review, we present an overview of the molecular basis of cardiac regeneration and describe current evidence implicating microRNAs and long noncoding RNAs in this process. Current limitations and future opportunities regarding how these regulatory mechanisms can be harnessed to study myocardial regeneration will be addressed.
Highlights
The heart is one of the most vital organs of the human body but at the same time forms one of the least adaptive organs in terms of regenerative capacity
Regeneration of the adult mammalian heart is limited, but recent findings have marked its capacity to recover from severe injury early after birth, and to renew cardiomyocytes throughout life
An increasing number of studies demonstrate that cardiomyocyte proliferation is under epigenetic control of the more recently emerged class of long noncoding RNAs (lncRNAs), such as ANRIL
Summary
The heart is one of the most vital organs of the human body but at the same time forms one of the least adaptive organs in terms of regenerative capacity. The human adult myocardium, like that of most mammalians, is incapable of adequate regeneration following cardiac injury. This failure to repair severe cardiomyocyte loss is a leading cause of heart failure and death worldwide [1]. Studies indicate that mammals even have the capability to overcome severe cardiomyocyte loss during neonatal life [4] These exciting findings gave rise to the idea that it might be possible to stimulate cardiac regeneration through cardiomyocyte proliferation in order to repair myocardial injury or treat failure. Gain- and loss-of-function studies show that modulation of specific miRNAs and lncRNAs holds promise to promote the regenerative capacity of the mammalian heart in small [9] and large [10] animal models. We describe the regenerative capacity of the newt, zebrafish, mouse, and human heart and describe similarities and differences between them
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