Editors' ChoiceCardiac Stem Cells

Genomic and Stem-Cell Technologies Collide

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Science Translational Medicine  11 Aug 2010:
Vol. 2, Issue 44, pp. 44ec125
DOI: 10.1126/scitranslmed.3001544

The Long-QT syndromes (LQTS) are familial disorders characterized by a heightened risk for death secondary to a dangerous arrhythmia known as polymorphic ventricular tachycardia. The genomic basis of LQTS has been linked to hundreds of mutations in 10 genes. The most common subtype of LQTS occurs in individuals harboring mutations in the gene KCNQ1 and accounts for 45% of all cases. This gene encodes the pore-forming units of the slow outward potassium K+ channel (IKs), with mutations resulting in a prolonged repolarization phase of the cardiac action potential and a prolonged QT interval on the electrocardiogram (ECG). However, to date the functional relevance of KCNQ1 mutations in LQTS1 has been largely unsubstantiated, given the difficulty in obtaining human myocardial tissue from individuals afflicted with this disorder.

Now, Moretti and colleagues offer a valuable and feasible alternative for obtaining human cardiomyocytes by using an induced pluripotent stem-cell model for LQTS. First, they obtained dermal biopsy samples from two related LQTS cases and healthy controls in order to generate pluripotent stem cells. The cells were then differentiated via standard stem-cell protocols and cardiomyocyte lineage confirmed through immunohistochemistry and reverse transcription polymerase chain reaction studies. Of note, sequencing of KCNQ1 in the affected family revealed the presence of a single missense mutation that resulted in a glutamine-for-arginine substitution (R190Q), which was confirmed to be present in the LQTS case but not in the control cardiomyocytes. They then documented LQTS1 cardiomyocytes to have reduced cell-surface expression of KCNQ1 when compared with wild-type cardiomyocytes. Moreover, comprehensive studies on individual LQTS1 cardiomyocytes revealed electrophysiologic features that are consistent with LQTS, including diminished current, prolonged AP duration, and early after-depolarizations (EAD) when given isoproterenol, which is a stimulant with potent effects on heart rate and contractility. Finally, these EADs—which predispose patients to polymprophic ventricular tachycardia—were prevented by administration of a commonly used β-blocker, propranolol. The results from this study marks the first time that pluripotent stem cells have been used to generate cardiomyocytes harboring a disease phenotype. Going forward, the collision of genomics and stem-cell technology has the potential to transform how we conduct studies to understand the mechanisms behind various genetic diseases and develop therapies to treat these disorders.

A. Moretti et al., Patient-specific induced pluripotent stem-cell models for Long-QT syndrome. 21 July 2010 (10.1056/NEJMoa0908679). [PubMed]

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