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Current Cardiology Reports

, 21:131 | Cite as

Cell Cycle–Mediated Cardiac Regeneration in the Mouse Heart

  • Arash Eghbali
  • Austin Dukes
  • Karl Toischer
  • Gerd Hasenfuss
  • Loren J. FieldEmail author
Regenerative Medicine (SM Wu, Section Editor)
  • 229 Downloads
Part of the following topical collections:
  1. Topical Collection on Regenerative Medicine

Abstract

Purpose of Review

Many forms of heart disease result in the essentially irreversible loss of cardiomyocytes. The ability to promote cardiomyocyte renewal may be a promising approach to reverse injury in diseased hearts. The purpose of this review is to describe the impact of cardiomyocyte cell cycle activation on cardiac function and structure in several different models of myocardial disease.

Recent Findings

Transgenic mice expressing cyclin D2 (D2 mice) exhibit sustained cardiomyocyte renewal in the adult heart. Earlier studies demonstrated that D2 mice exhibited progressive myocardial regeneration in experimental models of myocardial infarction, and that cardiac function was normalized to values seen in sham-operated litter mates by 180 days post-injury. D2 mice also exhibited markedly improved atrial structure in a genetic model of atrial fibrosis. More recent studies revealed that D2 mice were remarkably resistant to heart failure induced by chronic elevated afterload as compared with their wild type (WT siblings), with a 6-fold increase in median survival as well as retention of relatively normal cardiac function. Finally, D2 mice exhibited a progressive recovery in cardiac function to normal levels and a concomitant reduction in adverse myocardial remodeling in an anthracycline cardiotoxicity model.

Summary

The studies reviewed here make a strong case for the potential utility of inducing cardiomyocyte renewal as a means to treat injured hearts. Several challenges which must be met to develop a viable therapeutic intervention based on these observations are discussed.

Keywords

Cardiac regeneration Cardiomyocyte renewal Cell cycle regulation 

Notes

Author Contributions

Arash Eghbali and Austin Dukes contributed equally to this work.

Compliance with Ethical Standards

Conflict of Interest

Arash Eghbali, Austin Dukes, Karl Toischer, and Loren J. Field declare that they have no conflict of interest.

Gerd Hasenfuss reports personal fees from Corvia, Servier, Impulse Dynamics, Novartis, AstraZeneca, Vifor Pharma, Berlin Chemie, and Springer.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

References

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

  1. 1.
    Ali SR, Hippenmeyer S, Saadat LV, Luo L, Weissman IL, Ardehali R. Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proc Natl Acad Sci U S A. 2014;111(24):8850–5.  https://doi.org/10.1073/pnas.1408233111.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013;493(7432):433–6.  https://doi.org/10.1038/nature11682.CrossRefPubMedGoogle Scholar
  3. 3••.
    . Eschenhagen T, Bolli R, Braun T, Field LJ, Fleischmann BK, Frisen J, et al. Cardiomyocyte regeneration: a consensus statement. Circulation. 2017;136(7):680–6.  https://doi.org/10.1161/CIRCULATIONAHA.117.029343 This consensus statement delineates the lack of critical data supporting a direct cardiomyogenic role for purported cardiac resident stem cells, and thus underscores the need to develop alternative strategies for promoting myocardial regeneration. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Madonna R, Van Laake LW, Davidson SM, Engel FB, Hausenloy DJ, Lecour S, et al. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J. 2016;37(23):1789–98.  https://doi.org/10.1093/eurheartj/ehw113.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Phys. 1997;272(1 Pt 2):H220–6.Google Scholar
  6. 6.
    Soonpaa MH, Field LJ. Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res. 1998;83(1):15–26.CrossRefPubMedGoogle Scholar
  7. 7.
    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98–102.  https://doi.org/10.1126/science.1164680.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, et al. Dynamics of cell generation and turnover in the human heart. Cell. 2015;161(7):1566–75.  https://doi.org/10.1016/j.cell.2015.05.026.CrossRefPubMedGoogle Scholar
  9. 9.
    Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999;79(1):215–62.CrossRefPubMedGoogle Scholar
  10. 10.
    Pasumarthi KB, Field LJ. Cardiomyocyte cell cycle regulation. Circ Res. 2002;90(10):1044–54.CrossRefPubMedGoogle Scholar
  11. 11.
    Field LJ. Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. Science. 1988;239(4843):1029–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Behringer RR, Peschon JJ, Messing A, Gartside CL, Hauschka SD, Palmiter RD, et al. Heart and bone tumors in transgenic mice. Proc Natl Acad Sci U S A. 1988;85(8):2648–52.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Katz EB, Steinhelper ME, Delcarpio JB, Daud AI, Claycomb WC, Field LJ. Cardiomyocyte proliferation in mice expressing alpha-cardiac myosin heavy chain-SV40 T-antigen transgenes. Am J Phys. 1992;262(6 Pt 2):H1867–76.Google Scholar
  14. 14.
    Pasumarthi KB, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ Res. 2005;96(1):110–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Hassink RJ, Pasumarthi KB, Nakajima H, Rubart M, Soonpaa MH, de la Riviere AB, et al. Cardiomyocyte cell cycle activation improves cardiac function after myocardial infarction. Cardiovasc Res. 2008;78(1):18–25.CrossRefPubMedGoogle Scholar
  16. 16.
    Nakajima H, Nakajima HO, Dembowsky K, Pasumarthi KB, Field LJ. Cardiomyocyte cell cycle activation ameliorates fibrosis in the atrium. Circ Res. 2006;98(1):141–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Nakajima H, Nakajima HO, Salcher O, Dittie AS, Dembowsky K, Jing S, et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res. 2000;86(5):571–9.CrossRefPubMedGoogle Scholar
  18. 18•.
    . Toischer K, Zhu W, Hunlich M, Mohamed BA, Khadjeh S, Reuter SP, et al. Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload. J Clin Invest. 2017;127(12):4285–96.  https://doi.org/10.1172/JCI81870 Findings from this study suggest that the presence of cardiomyocyte cell cycle activity can block the onset of heart failure resulting from chronic increases in cardiac afterload. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19•.
    . Zhu W, Reuter S, Field LJ. Targeted expression of cyclin D2 ameliorates late stage anthracycline cardiotoxicity. Cardiovasc Res. 2019;115(5):960–5.  https://doi.org/10.1093/cvr/cvy273 Findings from this study demonstrate that the presence of cardiomyocyte cell cycle activity can reverse heart failure in a chronic juvenile doxorubicin cardiotoxicity model. CrossRefPubMedGoogle Scholar
  20. 20.
    Zhu W, Shou W, Payne RM, Caldwell R, Field LJ. A mouse model for juvenile doxorubicin-induced cardiac dysfunction. Pediatr Res. 2008;64(5):488–94.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Arash Eghbali
    • 1
  • Austin Dukes
    • 1
  • Karl Toischer
    • 2
    • 3
  • Gerd Hasenfuss
    • 2
    • 3
  • Loren J. Field
    • 1
    Email author
  1. 1.Krannert Institute of Cardiology and the Herman B Wells Center for Pediatric ResearchIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of Cardiology and Pneumology, Heart CenterGeorg-August-UniversityGoettingenGermany
  3. 3.DZHK (German Center for Cardiovascular Research) Partner Site GoettingenGoettingenGermany

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