Abstract
During the past few decades, there has been enormous progress made in understanding and treating cardiovascular diseases. However, heart failure remains a progressive and debilitating condition with generally poor clinical outcomes and high socio-economic burden. The most common cause of heart failure is caused by loss of functional cardiomyocytes from myocardial infarction and subsequent fibrosis, leading to adverse remodeling, reduced contractile function, and hemodynamic compromise. Given the dire need for better heart failure treatment, investigators have actively explored strategies to improve cardiac function via numerous approaches, including cell transplantation, mechanical device support, or whole organ replacement.1 Although a detailed comparison of the merit of each of these approaches is beyond the scope of this article, one strategy that has captured tremendous interest in recent years is the use of highly potent transcription factors to reprogram cells into an alternative fate. The remarkable finding of Yamanaka and colleagues to revert a fully differentiated cell back to its most primitive state using a combination of transcript factors brought forth widespread optimism that a similar approach can be used successfully to reprogram any somatic cell into a different cell type.2–5 This subsequently led to several follow-on studies to directly reprogram fibroblasts into other cell lineages.6,7 In 2010, one such study by Ieda, Srivastava, and colleagues described the generation of cardiomyocyte-like cells (iCM) by overexpressing Gata4, Mef2c, and Tbx5 (GMT), transcription factors that have been shown to play important roles in cardiac development.8 Although this study reported the generation of 5% to 10% troponin T expressing cells in vitro, 2 follow up studies by Qian et al9 and Song et al10 report the ability of GMT or GMT+Hand1 to reprogram resident cardiac fibroblasts within the failing/fibrotic myocardium into functional …
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