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Biochemistry (Moscow)

, Volume 84, Issue 3, pp 291–298 | Cite as

Applying Patient-Specific Induced Pluripotent Stem Cells to Create a Model of Hypertrophic Cardiomyopathy

  • E. V. DementyevaEmail author
  • S. P. Medvedev
  • V. R. Kovalenko
  • Yu. V. Vyatkin
  • E. I. Kretov
  • M. M. Slotvitsky
  • D. N. Shtokalo
  • E. A. Pokushalov
  • S. M. Zakian
Article
  • 13 Downloads

Abstract

Generation of patient-specific induced pluripotent stem cells (iPSCs) and their subsequent differentiation into cardiomyocytes opened new opportunities for studying pathogenesis of inherited cardiovascular diseases. One of these diseases is hypertrophic cardiomyopathy (HCM) for which no efficient therapy methods have been developed so far. In this study, the approach based on patient-specific iPSCs was applied to create a model of the disease. Genetic analysis of a hypertrophic cardiomyopathy patient revealed R326Q mutation in the MYBPC3 gene. iPSCs of the patient were generated and characterized. The cells were differentiated into cardiomyocytes together with the control iPSCs from a healthy donor. The patient’s iPSC-derived cardiomyocytes exhibited early HCM features, such as abnormal calcium handling and increased intracellular calcium concentration. Therefore, cardiomyocytes obtained by directed differentiation of iPSCs from the HCM patient can be used as a model system to study HCM pathogenesis.

Keywords

induced pluripotent stem cells human disease models hypertrophic cardiomyopathy cardiomyocytes 

Abbreviations

DAPI

4′,6-diamidino-2-phenylindole

HCM

hypertrophic cardiomyopathy

iPSCs

induced pluripotent stem cells

MLC2

ventricular form of the myosin light chain 2

MNCs

mononuclear cells

MYBPC3

cardiac myosin-binding protein C

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References

  1. 1.
    Maron, B. J. (2002) Hypertrophic cardiomyopathy: a sys–tematic review, JAMA, 287, 1308–1320.Google Scholar
  2. 2.
    Maron, B. J., Maron, M. S., and Semsarian, C. (2012) Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives, J. Am. Coll. Cardiol., 60, 705–715.CrossRefGoogle Scholar
  3. 3.
    Houston, B. A., and Stevens, G. R. (2014) Hypertrophic cardiomyopathy: a review, Clin. Med. Insights Cardiol., 8, 53–65.Google Scholar
  4. 4.
    Semsarian, C., Ingles, J., Maron, M. S., and Maron, B. J. (2015) New perspectives on the prevalence of hypertrophic cardiomyopathy, J. Am. Coll. Cardiol., 65, 1249–1254.CrossRefGoogle Scholar
  5. 5.
    Yang, Q., Sanbe, A., Osinska, H., Hewett, T. E., Klevitsky, R., and Robbins, J. (1998) A mouse model of myosin bind–ing protein C human familial hypertrophic cardiomyopa–thy, J. Clin. Invest., 102, 1292–1300.CrossRefGoogle Scholar
  6. 6.
    Marian, A. J., Wu, Y., Lim, D. S., McCluggage, M., Youker, K., Yu, Q. T., Brugada, R., DeMayo, F., Quinones, M., and Roberts, R. (1999) A transgenic rabbit model for human hypertrophic cardiomyopathy, J. Clin. Invest., 104, 1683–1692.CrossRefGoogle Scholar
  7. 7.
    Semsarian, C., Ahmad, I., Giewat, M., Georgakopoulos, D., Schmitt, J. P., McConnell, B. K., Reiken, S., Mende, U., Marks, A. R., Kass, D. A., Seidman, C. E., and Seidman, J. G. (2002) The L–type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model, J. Clin. Invest., 109, 1013–1020.CrossRefGoogle Scholar
  8. 8.
    Salama, G., and London, B. (2007) Mouse models of long QT syndrome, J. Physiol., 578, 43–53.CrossRefGoogle Scholar
  9. 9.
    Ross, S. B., Fraser, S. T., and Semsarian, C. (2016) Induced pluripotent stem cells in the inherited cardiomyo–pathies: from disease mechanisms to novel therapies, Trends Cardiovasc. Med., 26, 663–672.CrossRefGoogle Scholar
  10. 10.
    Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell, 126, 663–676.CrossRefGoogle Scholar
  11. 11.
    Yu, J., Vodyanik, M. A., Smuga–Otto, K., Antosiewicz–Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, I. I., and Thomson, J. A. (2007) Induced pluripotent stem cell lines derived from human somatic cells, Science, 318, 1917–1920.CrossRefGoogle Scholar
  12. 12.
    Lan, F., Lee, A. S., Liang, P., Sanchez–Freire, V., Nguyen, P. K., Wang, L., Han, L., Yen, M., Wang, Y., Sun, N., Abilez, O. J., Hu, S., Ebert, A. D., Navarrete, E. G., Simmons, C. S., Wheeler, M., Pruitt, B., Lewis, R., Yamaguchi, Y., Ashley, E. A., Bers, D. M., Robbins, R. C., Longaker, M. T., and Wu, J. C. (2013) Abnormal calcium handling properties underlie familial hypertrophic car–diomyopathy pathology in patient–specific induced pluripotent stem cells, Cell Stem Cell, 12, 101–113.CrossRefGoogle Scholar
  13. 13.
    Han, L., Li, Y., Tchao, J., Kaplan, A. D., Lin, B., Mich–Basso, J., Lis, A., Hassan, N., London, B., Bett, G. C., Tobita, K., Rasmusson, R. L., and Yang, L. (2014) Study familial hypertrophic cardiomyopathy using patient–specif–ic induced pluripotent stem cells, Cardiovasc. Res., 104, 258–269.CrossRefGoogle Scholar
  14. 14.
    Tanaka, A., Yuasa, S., Mearini, G., Egashira, T., Seki, T., Kodaira, M., Kusumoto, D., Kuroda, Y., Okata, S., Suzuki, T., Inohara, T., Arimura, T., Makino, S., Kimura, K., Kimura, A., Furukawa, T., Carrier, L., Node, K., and Fukuda, K. (2014) Endothelin–1 induces myofibrillar dis–array and contractile vector variability in hypertrophic car–diomyopathy–induced pluripotent stem cell–derived car–diomyocytes, J. Am. Heart Assoc., 3, e001263.Google Scholar
  15. 15.
    Medvedev, S. P., Grigor’eva, E. V., Shevchenko, A. I., Malakhova, A. A., Dementyeva, E. V., Shilov, A. A., Pokushalov, E. A., Zaidman, A. M., Aleksandrova, M. A., Plotnikov, E. Y., Sukhikh, G. T., and Zakian, S. M. (2011) Human induced pluripotent stem cells derived from fetal neural stem cells successfully undergo directed differentia–tion into cartilage, Stem Cells Dev., 20, 1099–1112.CrossRefGoogle Scholar
  16. 16.
    Burridge, P. W., Matsa, E., Shukla, P., Lin, Z. C., Churko, J. M., Ebert, A. D., Lan, F., Diecke, S., Huber, B., Mordwinkin, N. M., Plews, J. R., Abilez, O. J., Cui, B., Gold, J. D., and Wu, J. C. (2014) Chemically defined generation of human cardiomyocytes, Nat. Methods, 11, 855–860.CrossRefGoogle Scholar
  17. 17.
    Lian, X., Zhang, J., Azarin, S. M., Zhu, K., Hazeltine, L. B., Bao, X., Hsiao, C., Kamp, T. J., and Palecek, S. P. (2013) Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β–catenin signal–ing under fully defined conditions, Nat. Protoc., 8, 162–175.CrossRefGoogle Scholar
  18. 18.
    Slotvitsky, M. M., Tsvelaya, V. A., Frolova, S. R., Dement’eva, E. V., and Agladze, K. I. (2018) The study of the functionality of cardiomyocytes obtained from induced pluripotent stem cells for the modeling of cardiac arrhyth–mias based on long QT syndrome, Vavilov Zh. Genet. Selek., 22, 187–195.Google Scholar
  19. 19.
    Okita, K., Yamakawa, T., Matsumura, Y., Sato, Y., Amano, N., Watanabe, A., Goshima, N., and Yamanaka, S. (2013) An efficient nonviral method to generate integration–free human–induced pluripotent stem cells from cord blood and peripheral blood cells, Stem Cells, 31, 458–466.CrossRefGoogle Scholar
  20. 20.
    Valetdinova, K. R. (2016) Generating a Model System of Spinal Muscle Atrophy Using Human Induced Pluripotent Stem Cells: PhD theses [in Russian], ICG SB Russian Academy of Sciences, Novosibirsk.Google Scholar
  21. 21.
    Pasipoularides, A. (2018) Challenges and controversies in hypertrophic cardiomyopathy: clinical, genomic and basic science perspectives, Rev. Esp. Cardiol. (Engl. Ed.), 71, 132–138.CrossRefGoogle Scholar
  22. 22.
    Konno, T., Chang, S., Seidman, J. G., and Seidman, C. E. (2010) Genetics of hypertrophic cardiomyopathy, Curr. Opin. Cardiol., 25, 205–209.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • E. V. Dementyeva
    • 1
    • 2
    • 3
    Email author
  • S. P. Medvedev
    • 1
    • 2
    • 3
    • 4
  • V. R. Kovalenko
    • 1
    • 2
    • 3
    • 4
  • Yu. V. Vyatkin
    • 4
    • 5
  • E. I. Kretov
    • 2
  • M. M. Slotvitsky
    • 6
  • D. N. Shtokalo
    • 5
    • 7
  • E. A. Pokushalov
    • 2
  • S. M. Zakian
    • 1
    • 2
    • 3
    • 4
  1. 1.Federal Research Center Institute of Cytology and GeneticsSiberian Branch of the Russian Academy of SciencesNovosibirskRussia
  2. 2.Meshalkin National Medical Research CenterMinistry of Health of Russian FederationNovosibirskRussia
  3. 3.Institute of Chemical Biology and Fundamental MedicineSiberian Branch of the Russian Academy of SciencesNovosibirskRussia
  4. 4.Novosibirsk State UniversityNovosibirskRussia
  5. 5.Novel Software Systems LtdNovosibirskRussia
  6. 6.Moscow Institute of Physics and TechnologyDolgoprudny, Moscow RegionRussia
  7. 7.A. P. Ershov Institute of Informatics SystemsNovosibirskRussia

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