A human cell-based model has long been the holy grail of heart disease research. Historically, studies of cardiac physiology have relied heavily on animal models. Such models have been of great value, but they cannot fully emulate the complex phenotypes of many diseases. Moreover, the electrophysiological properties of the heart vary considerably across species. A human cell-based system would thus be uniquely valuable for elucidating both the pathogenesis of disease and the efficacy of prospective therapies.
In an article recently published in NEJM, Moretti et al report successfully developing patient-specific induced pluripotent stem cell (iPS) lines and then directing those stem cells to differentiate into functional heart muscle cells (cardiac myocytes). Just as in the human heart, these cardiac myocytes displayed “atrial,” “ventricular,” and “nodal” phenotypes, as characterized by their action potentials and expression of specific markers. Moreover, cardiac myocytes derived from patients with Long QT syndrome, a genetically based cardiac condition, recapitulated the signature electrophysiology of the disorder. These findings represent an exciting proof-of-concept and suggest that human stem cell-derived cardiac myocytes may be able to serve as a viable model for future study of genetic cardiac disorders.
Long QT syndrome is an autosomal dominant disease characterized by an abnormally prolonged ventricular repolarization phase. The disease often leads to polymorphic ventricular tachycardia and sudden cardiac death. Patients with long QT syndrome type 1 (LQT1), the most common form of the disease, carry an R190Q mutation in the KCNQ1 gene; this gene encodes a potassium channel that mediates the rectifier current involved in repolarization. It has been hypothesized that reduced outward potassium current through the KCNQ1 channel is responsible for the disease phenotype. One goal of this study was to determine whether the rectifier current density was actually different in cardiac myocytes derived from LQT1 patients as compared with controls.
To do this, Moretti et al developed patient-specific iPS lines using skin fibroblasts isolated from two healthy control patients and two patients from a family with LQT1. Cardiac myocytes derived from LQT1 patient fibroblasts maintained the specific genetic mutation observed in those patients. Moreover, in electrophysiological studies, the LQT1 cardiac myocytes showed a prolonged action potential as compared with the cardiac myocytes derived from control patients’ fibroblasts. The LQT1 cardiac myocytes also showed increased susceptibility to adrenergic-induced tachyarrhythmia, as well as phenotype attenuation with beta blockade. All of these findings are consistent with the well-know clinical disease phenotype for LQT1.
This study provides valuable insight into the pathogenesis of LQT1. More broadly, by successfully turning patients’ skin cells into stem cells and ultimately functional heart cells, it demonstrates the potential viability of human cell-based systems as a model for disease research.
In an accompanying editorial, Dr. Anthony Rosenzweig of Beth Israel Deaconess Medical Center and Associate Editor at NEJM writes, “Despite [many] challenges, patient-specific iPS-derived cellular models provide an important additional tool for the study of human disease. In cardiac conditions, where availability and viability of human cardiomyocytes have been limiting, iPS provides an unprecedented opportunity to study disease mechanisms and potential therapies in a human cellular context.” This study gives a whole new meaning to the idea of having “skin in the game.”
Given the technical challenges of working with iPS, do you think it will be feasible to develop patient-specific cellular models of disease on a large scale? Other than the study of genetic cardiac disorders, in what areas of research do you think iPS models will prove particularly useful?