Hippo in the Path to Heart Repair
The inability of the adult human heart to regenerate in response to injury, disease, and aging stands as a central challenge in cardiovascular medicine. Following myocardial infarction (MI), billions of cardiomyocytes are lost and replaced with an avascular fibrotic scar. Although various medical interventions have augmented survival rates after MI, the fibrotic myocardium mitigates cardiac contractility, leading to a poor long-term prognosis in these patients. Thus, there is an immense need for innovative approaches to repopulate lost cardiomyocytes following cardiac injury.
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In principle, several biological approaches to heart regeneration can be envisioned, including stem cell therapies, reprogramming of cardiac fibroblasts into cardiomyocytes, activation of cardiomyocyte proliferation, and suppression of fibrosis. However, each of these approaches faces uncertainties and challenges that have yet to be overcome. For example, although harnessing the potential of ostensible cardiac stem cells represents an attractive approach to repopulate lost cardiomyocytes, the process has proven to be, thus far, inefficient and tenuous because of the inability of stem cells to fully adopt a contractile phenotype, incomplete electrophysical integration into the myocardium, and inefficient long-term retention of transplanted cells.1–3 What is irrefutable is that the level of turnover of cardiomyocytes in adult mammals is inadequate to account for significant regeneration or functional restoration of the heart after severe injury.
Another approach to replenish myocytes after injury would be to convert resident cardiac fibroblasts directly into cardiomyocytes. Recently, it has been demonstrated that fibroblasts can be converted into cardiomyocytes in vitro with the viral addition of a cocktail of cardiac transcription factors.4 In related studies, forced expression of only 3 or 4 cardiac transcription factors was shown to be sufficient to induce cardiac gene expression in cardiac fibroblasts in vivo, which enhanced cardiac function and attenuated ventricular remodeling after MI.5 …