Cardiomyocyte Proliferation for Therapeutic Regeneration
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Purpose of Review
Current pharmacologic treatments for cardiovascular disease do not correct the underlying cellular defect, the loss of cardiomyocytes. With recent advancements in cardiac regenerative approaches, the induction of endogenous mature cardiomyocyte proliferation has emerged as a new possibility. Here, we review progress made toward the regeneration of cardiac tissue in the mammalian heart through the stimulation of mature cardiomyocyte renewal.
The targeting of several developmental and signaling pathways has been shown to stimulate cell cycle re-entry in mature cardiomyocytes. In animal models of cardiac regeneration, various strategies have been used to target these pathways to stimulate cardiomyocyte renewal and have relied on the delivery of signaling factors via systemic delivery, epicardial patches, or direct intramyocardial injection. Gene therapy techniques involving the viral delivery of transgenes by using adenoviral or adeno-associated viral vectors have been used to successfully target cardiac gene expression. The delivery of nucleic acids in the form of anti-microRNAs and microRNA mimetics has also been shown to be effective in stimulating cardiomyocyte renewal.
As the field of cardiac regeneration continues to progress, an important ongoing challenge in developing clinically translatable therapies is limiting the stimulation of growth pathways in non-cardiomyocytes.
KeywordsCardiomyocyte Regeneration Proliferation Cell cycle Heart failure Cardiovascular disease
We apologize to researchers whose work is not cited here because of space constraints. Nicole Stancel, PhD, ELS, of the Section of Scientific Publications at the Texas Heart Institute, provided editorial support.
Supported by the National Institutes of Health (DE 023177, HL 127717, HL 130804, and HL 118761 to J.F.M.), MacDonald Research Fund Award 16RDM001 (J.F.M.), and the Vivian L. Smith Foundation (J.F.M.). J.F.M. was supported by the LeDucq Foundation’s Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01: “Defining the Genomic Topology of Atrial Fibrillation”).
Compliance with Ethical Standards
Conflict of Interest
John P. Leach and James F. Martin report a patent US9732345B2 issued.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human subjects performed by any of the authors.
All mouse procedures were performed in accordance with institutional and governmental guidelines and were approved by the Baylor College of Medicine Institutional Animal Care and Use Committee.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
- 1.Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R et al. Heart disease and stroke statistics–2017 update: a report from the American Heart Association. Circulation 2017;135(10), e146, e603.Google Scholar
- 2.Braunwald E. Heart failure. JACC: Heart Fail. 2013;1(1):1–20.Google Scholar
- 5.Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Phys. 1996;271(5 Pt 2):9.Google Scholar
- 6.Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Phys. 1997;272(1 Pt 2):6.Google Scholar
- 11.• 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. This study used the MADM reporter to trace cell division in mature cardiomyocytes.–5.Google Scholar
- 22.Yahalom-Ronen Y, Rajchman D, Sarig R, Elife G-B. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion. Elife 2015, 4.Google Scholar
- 23.Woo YJ, Panlilio CM, Cheng RK, Liao GP, Atluri P, Hsu VM, et al. Therapeutic delivery of cyclin A2 induces myocardial regeneration and enhances cardiac function in ischemic heart failure. Circulation. 2006;114(1 Suppl):13.Google Scholar
- 24.Mohamed TMA, Ang YS, Radzinsky E, Zhou P, Huang Y, Elfenbein A, Foley A, Magnitsky S, Srivastava D Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 2018;173(1):104–16 e12, 116.e12.Google Scholar
- 26.Koudstaal S, Bastings MM, Feyen DA, Waring CD, van Slochteren FJ, Dankers PY, et al. Sustained delivery of insulin-like growth factor-1/hepatocyte growth factor stimulates endogenous cardiac repair in the chronic infarcted pig heart. J Cardiovasc Transl Res. 2014;7(2):232–41.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Bagno LL, of the … KT-RM. Growth hormone–releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy. Journal of the …. 2015.Google Scholar
- 28.Ladage D, Yaniz-Galende E, Rapti K, Ishikawa K, Tilemann L, Shapiro S, et al. Stimulating myocardial regeneration with periostin peptide in large mammals improves function post-myocardial infarction but increases myocardial fibrosis. PLoS One. 2013;8(5):e59656.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.•• Leach JP, Heallen T, Zhang M, Rahmani M, Morikawa Y, Hill MC et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 0500. This study describes a mouse model of systolic heart failure. Upon deletion of the Hippo pathway, protein Salvador in mice with established systolic heart failure cardiac function improves and over time reaches normal systolic function. Google Scholar
- 37.•• Bassat E, Mutlak YE, Genzelinakh A, Shadrin IY, Baruch Umansky K, Yifa O, Kain D, Rajchman D, Leach J, Riabov Bassat D, Udi Y, Sarig R, Sagi I, Martin JF, Bursac N, Cohen S, Tzahor E The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 2017;547(7662):179–84. This study demonstrates the utility of a matrix protein, Agrin, to stimulate cardiomyocyte prolieration through an interaction with the dystroglycan complex. Google Scholar
- 44.O'Donoghue ML, Glaser R, Cavender MA, Jama APE. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA 2016, 315, 1591, 1599.Google Scholar
- 54.•• Morikawa Y, Heallen T, Leach J, Xiao Y, Martin JF. Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 2017;547(7662):227–31. This study describes a novel interaction between the Hippo signaling effector Yap and the dystroglycan complex to limit cardiomyocyte proliferation. Google Scholar