hiPSC Modeling of Inherited Cardiomyopathies

  • Gwanghyun Jung
  • Daniel BernsteinEmail author
Regenerative Medicine and Stem-cell Therapy (S Wu and P Hsieh, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Regenerative Medicine and Stem-cell Therapy

Opinion statement

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.


Dilated 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

  1. 1.
    Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010;363:1397–409.PubMedCrossRefGoogle Scholar
  2. 2.
    Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature. 2011;471:230–4.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ma D, Wei H, Lu J, Ho S, Zhang G, Sun X, et al. Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2013;34:1122–33.PubMedCrossRefGoogle Scholar
  4. 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
  5. 5.
    Lan F, Lee AS, Liang P, Sanchez-Freire V, Nguyen PK, Wang L, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013;12:101–13.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Carvajal-Vergara X, Sevilla A, D'Souza SL, Ang YS, Schaniel C, Lee DF, et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature. 2010;465:808–12.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 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
  8. 8.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.PubMedCrossRefGoogle Scholar
  9. 9.
    Denning C, Anderson D. Cardiomyocytes from human embryonic stem cells as predictors of cardiotoxicity. Drug Discov Today Ther Strateg. 2008;5:223–32.CrossRefGoogle Scholar
  10. 10.
    Merkle FT, Eggan K. Modeling human disease with pluripotent stem cells: from genome association to function. Cell Stem Cell. 2013;12:656–68.PubMedCrossRefGoogle Scholar
  11. 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
  12. 12.
    Siu CW, Lee YK, Ho JC, Lai WH, Chan YC, Ng KM, et al. Modeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells. Aging. 2012;4:803–22.PubMedCentralPubMedGoogle Scholar
  13. 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
  14. 14.
    Hick A, Wattenhofer-Donze M, Chintawar S, Tropel P, Simard JP, Vaucamps N, et al. Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich's ataxia. Dis Model Mech. 2013;6:608–21.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Dudek J, Cheng IF, Balleininger M, Vaz FM, Streckfuss-Bomeke K, Hubscher D, et al. Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome. Stem Cell Res. 2013;11:806–19.PubMedCrossRefGoogle Scholar
  16. 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
  17. 17.
    Huang HP, Chen PH, Hwu WL, Chuang CY, Chien YH, Stone L, et al. Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification. Hum Mol Genet. 2011;20:4851–64.PubMedCrossRefGoogle Scholar
  18. 18.
    Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 1998;98:1329–34.PubMedCrossRefGoogle Scholar
  19. 19.
    Wu CF, Bishopric NH, Pratt RE. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem. 1997;272:14860–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Snopko RM, Ramos-Franco J, Di Maio A, Karko KL, Manley C, Piedras-Renteria E, et al. Ca2+ sparks and cellular distribution of ryanodine receptors in developing cardiomyocytes from rat. J Mol Cell Cardiol. 2008;44:1032–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Gherghiceanu M, Barad L, Novak A, Reiter I, Itskovitz-Eldor J, Binah O, et al. Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: comparative ultrastructure. J Cell Mol Med. 2011;15:2539–51.PubMedCrossRefGoogle Scholar
  22. 22.
    Snir M, Kehat I, Gepstein A, Coleman R, Itskovitz-Eldor J, Livne E, et al. Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am J Physiol Heart Circ Physiol. 2003;285:H2355–63.PubMedGoogle Scholar
  23. 23.
    Lieu DK, Liu J, Siu CW, McNerney GP, Tse HF, Abu-Khalil A, et al. Absence of transverse tubules contributes to non-uniform Ca(2+) wavefronts in mouse and human embryonic stem cell-derived cardiomyocytes. Stem Cells Dev. 2009;18:1493–500.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Baharvand H, Ashtiani SK, Valojerdi MR, Shahverdi A, Taee A, Sabour D. Establishment and in vitro differentiation of a new embryonic stem cell line from human blastocyst. Differ Res Biol Divers. 2004;72:224–9.CrossRefGoogle Scholar
  25. 25.
    Haase A, Olmer R, Schwanke K, Wunderlich S, Merkert S, Hess C, et al. Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell. 2009;5:434–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Yamada KA, Rogers JG, Sundset R, Steinberg TH, Saffitz J. Up-regulation of connexin45 in heart failure. J Cardiovasc Electrophysiol. 2003;14:1205–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Blazeski A, Zhu R, Hunter DW, Weinberg SH, Zambidis ET, Tung L. Cardiomyocytes derived from human induced pluripotent stem cells as models for normal and diseased cardiac electrophysiology and contractility. Prog Biophys Mol Biol. 2012;110:166–77.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Braam SR, Tertoolen L, van de Stolpe A, Meyer T, Passier R, Mummery CL. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res. 2010;4:107–16.PubMedCrossRefGoogle Scholar
  29. 29.
    Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107:2733–40.PubMedCrossRefGoogle Scholar
  30. 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
  31. 31.
    Germanguz I, Sedan O, Zeevi-Levin N, Shtrichman R, Barak E, Ziskind A, et al. Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J Cell Mol Med. 2011;15:38–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Satin J, Itzhaki I, Rapoport S, Schroder EA, Izu L, Arbel G, et al. Calcium handling in human embryonic stem cell-derived cardiomyocytes. Stem Cells. 2008;26:1961–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Ziman AP, Gomez-Viquez NL, Bloch RJ, Lederer WJ. Excitation-contraction coupling changes during postnatal cardiac development. J Mol Cell Cardiol. 2010;48:379–86.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Zhang GQ, Wei H, Lu J, Wong P, Shim W. Identification and characterization of calcium sparks in cardiomyocytes derived from human induced pluripotent stem cells. PLoS One. 2013;8:e55266.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Fujiwara M, Yan P, Otsuji TG, Narazaki G, Uosaki H, Fukushima H, et al. Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A. PLoS One. 2011;6:e16734.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Novak A, Barad L, Zeevi-Levin N, Shick R, Shtrichman R, Lorber A, et al. Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to beta-adrenergic stimulation. J Cell Mol Med. 2012;16:468–82.PubMedCrossRefGoogle Scholar
  37. 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
  38. 38.
    Norman JJ, Mukundan V, Bernstein D, Pruitt BL. Microsystems for biomechanical measurements. Pediatr Res. 2008;63:576–83.PubMedCrossRefGoogle Scholar
  39. 39.
    Liu J, Sun N, Bruce MA, Wu JC, Butte MJ. Atomic force mechanobiology of pluripotent stem cell-derived cardiomyocytes. PLoS One. 2012;7:e37559.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Taylor RE, Kim K, Sun N, Park SJ, Sim JY, Fajardo G, et al. Sacrificial layer technique for axial force post assay of immature cardiomyocytes. Biomed Microdevices. 2013;15:171–81.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, et al. A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS ONE. 2011;6:e18293.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    White MP, Rufaihah AJ, Liu L, Ghebremariam YT, Ivey KN, Cooke JP, et al. Limited gene expression variation in human embryonic stem cell and induced pluripotent stem cell-derived endothelial cells. Stem Cells. 2013;31:92–103.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 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
  44. 44.
    Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467:285–90.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010;28:848–55.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Rao C, Prodromakis T, Kolker L, Chaudhry UA, Trantidou T, Sridhar A, et al. The effect of microgrooved culture substrates on calcium cycling of cardiac myocytes derived from human induced pluripotent stem cells. Biomaterials. 2013;34:2399–411.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Chan YC, Ting S, Lee YK, Ng KM, Zhang J, Chen Z, et al. Electrical stimulation promotes maturation of cardiomyocytes derived from human embryonic stem cells. J Cardiovasc Transl Res. 2013;6:989–99.PubMedCrossRefGoogle Scholar
  48. 48.
    Lundy SD, Zhu WZ, Regnier M, Laflamme MA. Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev. 2013;22:1991–2002.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 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

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Cardiology, Department of PediatricsStanford UniversityStanfordUSA
  2. 2.Stanford Cardiovascular InstituteStanford UniversityStanfordUSA
  3. 3.Palo AltoUSA

Personalised recommendations