MicroRNAs and cardiac regeneration
Feb 27, 2025
Authors
Conrad P Hodgkinson, Martin H Kang, Sophie Dal-Pra, Maria Mirotsou, Victor J Dzau
The human heart has a very limited capacity to regenerate lost or damaged cardiomyocytes following cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structure and function. Cardiac function would be improved if these fibroblasts could be converted into cardiomyocytes. MicroRNAs (miRNAs), small non-coding RNAs that promote mRNA degradation and inhibit mRNA translation, have been shown to be important in cardiac development. Using this information various researchers have utilized miRNAs to promote the formation of cardiomyocytes through a number of approaches. Several miRNAs acting in combination promote the direct conversion of cardiac fibroblasts into cardiomyocytes. Moreover, a number of miRNAs have been identified that aid the formation of iPS cells and miRNAs also induce these cells to adopt a cardiac fate. MiRNAs have also been implicated in resident cardiac progenitor cell differentiation. In this review we will discuss the current literature as it pertains to these processes as well as discussing the therapeutic implications of these findings.
Keywords: MicroRNA, regeneration, transdifferentiation, stem cell, cardiac myocyte
Introduction
Myocardial infarction leads to significant cardiomyocyte cell death. These specialized cells are not replaced in substantial numbers following injury leading to disproportionate thinning of the heart wall and severely impaired cardiac function. Moreover cardiac fibroblasts, which form a significant proportion of the heart, are expanded further leading to excessive fibrosis and scar formation. Fibrotic remodeling of the injured myocardium negatively impacts contractility and electrical conduction which over time causes a further deterioration in cardiac function (1.
A number of strategies are being actively pursued in cardiac regenerative medicine. Replacing lost cardiomyocytes by injecting cardiac progenitors, cardiospheres, or cardiac myocytes derived from inducible pluripotent stem cells and/or embryonic stem cells (iPS/ESCs) has been researched intensively. Others have focused instead on the cardiomyocytes by enabling them to enter cell cycle to replicate and proliferate as a means to generate new muscle cells. However, these approaches, while encouraging, face significant challenges. Recently, much excitement has been turned to the cardiac fibroblast population in the scar tissue with a view to turning these cells into cardiomyocytes 2. Taking cues from heart developmental programs 3–5 direct reprogramming of fibroblasts to cardiomyocytes has been achieved recently by specific combinations of transcription factors 6–8 and microRNAs (miRNAs) 2, 9–11.
In this review we will discuss the role of miRNAs in cardiac development as well as in indirect and direct cardiac reprogramming. Based on this scientific knowledge we will discuss the strategy of targeting miRNAs for cardiac regeneration therapy.
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