Patient-Specific Induced Pluripotent Stem Cells as a Model for Familial Dilated Cardiomyopathy

Human induced pluripotent stem cells generated from patients with familial dilated cardiomyopathy model cardiovascular disease in these patients. iPSCs Make the Heart Beat Faster Mutations in genes expressed in the heart can cause dilated cardiomyopathy (DCM), a form of heart disease in which a weakened and enlarged heart is unable to pump sufficient blood for the body’s needs. DCM can lead to progressive heart failure that eventually requires heart transplantation. This disease has been challenging to study because cardiomyocytes from the hearts of DCM patients are difficult to obtain and do not survive long. Mouse models of DCM are established and have provided important clues about the disease mechanisms for DCM. However, the mouse heart is very different in physiology compared to the human heart; for example, the mouse heart rate is 10 times faster than that of human. In a new study, Sun et al. generated induced pluripotent stem cells (iPSCs) from skin cells of patients in a family with inherited DCM. This family carries a deleterious mutation in TNNT2, a gene that is expressed specifically in the heart and regulates cardiomyocyte contraction. Using iPSCs, the authors generated a large number of individual-specific cardiomyocytes carrying the specific TNNT2 mutation and analyzed their functional properties. Compared to cardiomyocytes derived from iPSCs of healthy controls in the same family, cardiomyocytes derived from iPSCs of DCM patients exhibited an increased heterogeneous myofilament organization, susceptibility to stress, compromised ability to regulate calcium flux, and decreased contraction force. These results suggest that the mutation in TNNT2 causes abnormalities in the cardiomyocytes and contributes to the development of DCM disease. Using these DCM iPSC–derived cardiomyocytes, the researchers also showed that several current treatments that clinically benefit DCM disease improved DCM cardiomyocyte function in culture. The current study shows that human iPSC-derived cardiomyocytes could provide an important platform to investigate the specific disease mechanisms of DCM as well as other inherited cardiovascular disorders and for screening new drugs for cardiovascular disease. Characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure, dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy in patients. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific cellular models, investigating underlying mechanisms, and optimizing therapy. Here, we generated cardiomyocytes from iPSCs derived from patients in a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to control healthy individuals in the same family cohort, cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca2+), decreased contractility, and abnormal distribution of sarcomeric α-actinin. When stimulated with a β-adrenergic agonist, DCM iPSC–derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric α-actinin distribution. Treatment with β-adrenergic blockers or overexpression of sarcoplasmic reticulum Ca2+ adenosine triphosphatase (Serca2a) improved the function of iPSC-derived cardiomyocytes from DCM patients. Thus, iPSC-derived cardiomyocytes from DCM patients recapitulate to some extent the morphological and functional phenotypes of DCM and may serve as a useful platform for exploring disease mechanisms and for drug screening.