The successful derivation of human induced pluripotent stem cells (hiPSCs) from somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC-derived cardiac cells can now provide incredible potential for disease modeling in vitro and regenerative medicine therapies in vivo. Recently, several exciting demonstrations of the disease modeling capability of hiPSC- derived cardiac cells have been published (e.g., Timothy syndrome, LEOPARD syndrome). These patient-specific hiPSC-CMs have been found to recapitulate the disease phenotypes. In contrast to Timothy and LEOPARD syndrome (which are considered orphan diseases), familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and hence places a tremendous burden on the healthcare system in the US and worldwide. Here we seek to derive hiPSCs from patients with familial dilated cardiomyopathy (Aim 1), determine the phenotype of hiPSC-cardiac cells from DCM patients versus healthy controls (Aim 2), and evaluate their functionality after genetic rescue using homologous recombination (Aim 3). We believe the findings here should have broad clinical and scientific impact toward better understanding on the molecular and cellular basis of DCM.

Public Health Relevance

Familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and places a tremendous burden on the healthcare system in the US and worldwide. From the early beginnings of the genomic era and since the description of the first familial DCM causing mutations, investigators have attempted to study its mechanistic basis by correlating genotype with clinical phenotype expression. Unfortunately, these studies have been severely hampered by the inaccessibility of human cardiomyocytes. In this grant proposal, we will generate human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with DCM. We will perform detailed and mechanistic analyses to determine the functional and molecular phenotypes of DCM. This approach will dramatically enhance our ability to perform future high-throughput drug screening, evaluate gene and cell therapies, and assess potential novel therapies of DCM.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Buxton, Denis B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Sallam, Karim; Kodo, Kazuki; Wu, Joseph C (2014) Modeling inherited cardiac disorders. Circ J 78:784-94
Burridge, Paul W; Matsa, Elena; Shukla, Praveen et al. (2014) Chemically defined generation of human cardiomyocytes. Nat Methods 11:855-60
Matsa, Elena; Sallam, Karim; Wu, Joseph C (2014) Cardiac stem cell biology: glimpse of the past, present, and future. Circ Res 114:21-7
Dewey, Frederick E; Grove, Megan E; Pan, Cuiping et al. (2014) Clinical interpretation and implications of whole-genome sequencing. JAMA 311:1035-45
Sharma, Arun; Marceau, Caleb; Hamaguchi, Ryoko et al. (2014) Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform. Circ Res 115:556-66
Wang, Yongming; Liang, Ping; Lan, Feng et al. (2014) Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing. J Am Coll Cardiol 64:451-9
Ebert, Antje D; Kodo, Kazuki; Liang, Ping et al. (2014) Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system. Sci Transl Med 6:255ra130
Durruthy-Durruthy, Jens; Briggs, Sharon F; Awe, Jason et al. (2014) Rapid and efficient conversion of integration-free human induced pluripotent stem cells to GMP-grade culture conditions. PLoS One 9:e94231
Karakikes, Ioannis; Termglinchan, Vittavat; Wu, Joseph C (2014) Human-induced pluripotent stem cell models of inherited cardiomyopathies. Curr Opin Cardiol 29:214-9
Matsa, Elena; Burridge, Paul W; Wu, Joseph C (2014) Human stem cells for modeling heart disease and for drug discovery. Sci Transl Med 6:239ps6

Showing the most recent 10 out of 25 publications