A Better Pacemaker: Transdifferentiation of Myocytes to Pacemaker Cells

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Science Translational Medicine  09 Jan 2013:
Vol. 5, Issue 167, pp. 167ec7
DOI: 10.1126/scitranslmed.3005597

Implantable pacemakers are a major milestone in cardiovascular medicine. In the past 50 years, they have saved the lives of many patients in which the sinoatrial node—the primary source of the heart’s electrical stimulation—was dysfunctional or electrical conduction was blocked. Despite their increasingly smaller size and higher reliability, the implanted devices come with risks. Wires may break; batteries may run out. New work by Kapoor et al. brings us closer to deploying a biological pacemaker that does not have these shortcomings.

By overexpressing the transcription factor Tbx18, which is highly active in sinoatrial pacemaker cells, the authors were able to transdifferentiate cardiomyocytes into pacemaker cells. The transdifferentiated cells had the epigenetic, morphologic, and physiological properties of sinoatrial cells; started to express the necessary ion channels; and began pacing at physiological rates. After injection of a Tbx18-carrying adenoviral vector into the apex of guinea pig hearts, the transcription factor was robustly expressed. Several days later, in 5 out of 7 animals, an ectopic ventricular rhythm was detected. The transfected cells responded appropriately to adrenergic and muscarinic stimuli by increasing or decreasing the heart rate, an important feedback mechanism that adjusts cardiac output to physical activity. Six to 8 weeks after injection, the transcription of Tbx18 ceased; nevertheless, the pacemaker cell phenotype was stable. This direct conversion from cardiomyocytes to pacemaker cells in vivo is a big step forward toward the creation of biological pacemakers.

N. Kapoor, W. Liang, E. Marbán, H. Cheol Cho, Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat. Biotech., published online 16 December 2012 (10.1038/nbt.2465). [Abstract]

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