hiPSC Modeling of Inherited Cardiomyopathies
- 372 Downloads
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a powerful new model system to study the basic mechanisms of inherited cardiomyopathies. hiPSC-CMs have been utilized to model several cardiovascular diseases, achieving the most success in the inherited arrhythmias, including long QT and Timothy syndromes (Moretti et al. N Engl J Med. 363:1397–409, 2010; Yazawa et al. Nature. 471:230–4, 2011) and arrhythmogenic right ventricular dysplasia (ARVD) (Ma et al. Eur Heart J. 34:1122–33, 2013). Recently, studies have applied hiPSC-CMs to the study of both dilated (DCM) (Sun et al. Sci Transl Med. 4:130ra47, 2012) and hypertrophic (HCM) cardiomyopathies (Lan et al. Cell Stem Cell. 12:101–13, 2013; Carvajal-Vergara et al. Nature. 465:808–12, 2010), providing new insights into basic mechanisms of disease. However, hiPSC-CMs do not recapitulate many of the structural and functional aspects of mature human cardiomyocytes, instead mirroring an immature – embryonic or fetal – phenotype. Much work remains in order to better understand these differences, as well as to develop methods to induce hiPSC-CMs into a fully mature phenotype. Despite these limitations, hiPSC-CMs represent the best current in vitro correlate of the human heart and an invaluable tool in the search for mechanisms underlying cardiomyopathy and for screening new pharmacologic therapies.
KeywordsDilated cardiomyopathy Hypertrophic cardiomyopathy Arrhythmia Stem cells Induced pluripotent stem cells Cardiomyocytes Contractility Development
Compliance with Ethics Guidelines
Conflict of Interest
Dr. Gwanghyun Jung received a grant from Spectrum Child Health at Packard Children's Hospital at Stanford.
Dr. Daniel Bernstein received a grant from the National Institutes of Health.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 4.••Sun N, Yazawa M, Liu J, Han L, Sanchez-Freire V, Abilez OJ, et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med. 2012;4:130ra47. This study describes the first successful modeling of dilated cardiomyopathy in hiPSC-CMs. Familial dilated cardiomyopathy with inherited mutation in troponin T was recapitulated in vitro showing impaired contraction.PubMedCentralPubMedCrossRefGoogle Scholar
- 7.••Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72. This is one of the ground-breaking reports from Shinya Yamanaka's group demonstrating the ability to reprogram adult human cells into pluripotent stem cells, ultimately leading to his receiving the Nobel Prize in Physiology or Medicine along with John Gurdon in 2012.PubMedCrossRefGoogle Scholar
- 11.••Liang P, Lan F, Lee AS, Gong T, Sanchez-Freire V, Wang Y, et al. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation. 2013;127:1677–91. Using a collection of hiPSC-CMs from patients with inheried cardiac disorders, this study demonstrated patient-specific differential drug activity and drug cardiotoxicity, suggesting the possibility of using hiPSC-CMs for personalized drug screening.PubMedCrossRefGoogle Scholar
- 13.Tse HF, Ho JC, Choi SW, Lee YK, Butler AW, Ng KM, et al. Patient-specific induced-pluripotent stem cells-derived cardiomyocytes recapitulate the pathogenic phenotypes of dilated cardiomyopathy due to a novel DES mutation identified by whole exome sequencing. Hum Mol Genet. 2013;22:1395–403.PubMedCrossRefGoogle Scholar
- 16.Wang G, McCain ML, Yang L, He A, Pasqualini FS, Agarwal A, et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-chip technologies. Nat Med. 2014;in press.Google Scholar
- 30.de Sousa C, Lopes SM, Hassink RJ. Feijen A, van Rooijen MA, Doevendans PA, Tertoolen L, et al. Patterning the heart, a template for human cardiomyocyte development. Dev Dyn Off Publ Am Assoc Anat. 2006;235:1994–2002.Google Scholar
- 37.Pillekamp F, Haustein M, Khalil M, Emmelheinz M, Nazzal R, Adelmann R, et al. Contractile properties of early human embryonic stem cell-derived cardiomyocytes: beta-adrenergic stimulation induces positive chronotropy and lusitropy but not inotropy. Stem Cells Dev. 2012;21:2111–21.PubMedCrossRefGoogle Scholar
- 43.••Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T, et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2013;12:127–37. Increasing the purity of differentiated cardiomyocytes in vitro is a key issue for furthering the field of hiPSC-CM research. These authors demonstrated improvement of cardiomyocyte sorting based on differences in glucose and lactate metabolism, yielding cardiomyocyte populations of extremely high purity.PubMedCrossRefGoogle Scholar
- 49.••Dambrot C, Passier R, Atsma D, Mummery CL. Cardiomyocyte differentiation of pluripotent stem cells and their use as cardiac disease models. Biochem J. 2011;434:25–35. This review article, from one of the leaders in the field, provides a well-written, comprehensive review of stem cell techniques useful in cardiovascular research.PubMedCrossRefGoogle Scholar