Non-coding RNAs: emerging players in cardiomyocyte proliferation and cardiac regeneration
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REVIEW
Non‑coding RNAs: emerging players in cardiomyocyte proliferation and cardiac regeneration Naisam Abbas1 · Filippo Perbellini1 · Thomas Thum1 Received: 4 June 2020 / Accepted: 22 July 2020 © The Author(s) 2020
Abstract Soon after birth, the regenerative capacity of the mammalian heart is lost, cardiomyocytes withdraw from the cell cycle and demonstrate a minimal proliferation rate. Despite improved treatment and reperfusion strategies, the uncompensated cardiomyocyte loss during injury and disease results in cardiac remodeling and subsequent heart failure. The promising field of regenerative medicine aims to restore both the structure and function of damaged tissue through modulation of cellular processes and regulatory mechanisms involved in cardiac cell cycle arrest to boost cardiomyocyte proliferation. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are functional RNA molecules with no protein-coding function that have been reported to engage in cardiac regeneration and repair. In this review, we summarize the current understanding of both the biological functions and molecular mechanisms of ncRNAs involved in cardiomyocyte proliferation. Furthermore, we discuss their impact on the structure and contractile function of the heart in health and disease and their application for therapeutic interventions. Keywords Heart regeneration · Cardiomyocyte proliferation · MicroRNAs · lncRNAs · circRNAs
Introduction Heart failure is a burgeoning health problem worldwide. Often a consequence of cardiovascular events, heart failure has become a major cause of morbidity and mortality and its incidence is expected to grow further in the future [137]. Upon cardiac injury, the adult mammalian heart does not regenerate sufficiently to compensate for the lost myocardium, resulting in a cardiomyocyte deficiency, and hence a lack of functional recovery of the infarcted or failing heart. Therefore, there is an unmet need to device effective regenerative strategies to induce cardiomyocyte renewal and replace the post-infarct fibrotic tissue with contractile muscle cells. For many years, the human heart has been considered a post-mitotic and fully differentiated organ; this paradigm, * Filippo Perbellini Perbellini.Filippo@mh‑hannover.de * Thomas Thum Thum.Thomas@mh‑hannover.de 1
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hanover, Germany
however, has been challenged since various studies have reported a residual capacity of cardiomyocytes to proliferate after birth [8, 120]. This process has been shown to occur at a low rate and it progressively and continuously declines with age so much so that in a 60 years old human heart it does not exceed 0.5% [8]. On the contrary, other species such as zebrafish and newt can completely regenerate their hearts after myocardial injury by activating cardiomyocyte proliferation [4, 71]. Similarly, neonatal mammals such as rodents and pigs show some degree of regen
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