Low Regenerative Capability of Cardiomyocytes Heart failure affects about 8 million Americans of all ages every year. It considerably reduces quality of life with only a 50% five-year survival rate. Recent therapeutic approaches (drug development, cell transplantation, or heart transplantation) have a limited effect on treating cardiovascular disorders. Heart diseases occur mainly because cardiomyocytes have a low regenerative capability to replace damaged heart cells. After myocardial infarction, fibroblasts represent most cells in the damaged area and thus, constitute an ideal source of cells for reprogramming into cardiomyocytes. Direct reprogramming of cardiac fibroblasts to cardiomyocytes is a promising strategy that has made significant progress in the recent years. However, the main challenge remains the low efficiency of the technique.
TGF-β inhibitor University of Colorado research group led by Dr. Kunhua Song has developed a new technique to restore heart function by regeneration of cardiomyocytes. The group first demonstrated that, in addition to overexpression of cardiac development transcription factors (including GATA4, Hand2, Mef2c, and Tbx5), inhibition of profibrotic signaling dramatically increases reprogramming efficiency. Using the new methods, about 60% of fibroblasts express cardiac Troponin T (cTnT) and about 50% express α-actinin. Beating cardiomyocytes are observed in less than 2 weeks (Fig.1). Dr. Song’s group then effectively converted fibroblasts into cardiomyocytes in an intact beating rodent heart using an adeno-associated virus-based gene delivery method. About 80% of fibroblasts are transduced after a single injection. This new method allows a high conversion rate of fibroblasts into cardiomyocytes and reduces cardiac fibrosis.
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