Skip to main content

Advertisement

SpringerLink
Log in

hiPSC Modeling of Inherited Cardiomyopathies

  • Regenerative Medicine and Stem-cell Therapy (S Wu and P Hsieh, Section Editors)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  9. Denning C, Anderson D. Cardiomyocytes from human embryonic stem cells as predictors of cardiotoxicity. Drug Discov Today Ther Strateg. 2008;5:223–32.

    Article  Google Scholar 

  10. Merkle FT, Eggan K. Modeling human disease with pluripotent stem cells: from genome association to function. Cell Stem Cell. 2013;12:656–68.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google 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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Wu CF, Bishopric NH, Pratt RE. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem. 1997;272:14860–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  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 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

  38. Norman JJ, Mukundan V, Bernstein D, Pruitt BL. Microsystems for biomechanical measurements. Pediatr Res. 2008;63:576–83.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, CA, USA

    Gwanghyun Jung PhD & Daniel Bernstein MD

  2. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA

    Gwanghyun Jung PhD & Daniel Bernstein MD

  3. 750 Welch Road Suite 325, Palo Alto, CA, 94304, USA

    Daniel Bernstein MD

Authors
  1. Gwanghyun Jung PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Bernstein MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Bernstein MD.

Additional information

This article is part of the Topical Collection on Regenerative Medicine and Stem-cell Therapy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, G., Bernstein, D. hiPSC Modeling of Inherited Cardiomyopathies. Curr Treat Options Cardio Med 16, 320 (2014). https://doi.org/10.1007/s11936-014-0320-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11936-014-0320-7

Keywords

Search

Navigation