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Mechanisms of Neonatal Heart Regeneration

  • Regenerative Medicine (SM Wu, Section Editor)
  • Published:
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Abstract

Purpose of Review

This review provides an overview of the molecular mechanisms underpinning the cardiac regenerative capacity during the neonatal period and the potential targets for developing novel therapies to restore myocardial loss.

Recent Findings

We present recent advances in the understanding of the molecular mechanisms of neonatal cardiac regeneration and the implications for the development of new cardiac regenerative therapies. During the early postnatal period, several cell types and pathways are involved in cardiomyocyte proliferation including immune response, nerve signaling, extracellular matrix, mitochondria substrate utilization, gene expression, miRNAs, and cell cycle progression.

Summary

The early neonatal mammalian heart has remarkable regenerative capacity, which is mediated by proliferation of endogenous cardiomyocytes, and is lost when cardiomyocytes stop dividing shortly after birth. A wide array of mechanisms that regulate this regenerative process have been proposed.

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References

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

  1. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331:1078–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Porrello ER, Mahmoud AI, Simpson E, Johnson BA, Grinsfelder D, Canseco D, et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A. 2013;110:187–92.

    Article  CAS  PubMed  Google Scholar 

  3. Mahmoud AI, Kocabas F, Muralidhar SA, Kimura W, Koura AS, Thet S, et al. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature. 2013;497:249–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Phys. 1996;271:H2183–9.

    CAS  Google Scholar 

  5. Ye L, D’Agostino G, Loo SJ, Wang CX, Su LP, Tan SH, et al. Early regenerative capacity in the porcine heart. Circulation. 2018;138:2798–808.

    Article  PubMed  Google Scholar 

  6. Zhu W, Zhang E, Zhao M, Chong Z, Fan C, Tang Y, et al. Regenerative potential of neonatal porcine hearts. Circulation. 2018;138:2809–16.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Elhelaly WM, Cardoso AC, Pereira AHM, Elnawasany A, Ebrahimi S, Nakada Y, et al. C-kit cells do not significantly contribute to cardiomyogenesis during neonatal heart regeneration. Circulation. 2019;139:559–61.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bergmann O, Zdunek S, Frisen J, Bernard S, Druid H, Jovinge S. Cardiomyocyte renewal in humans. Circ Res. 2012;110:e17–8 author reply e19-21.

    Article  CAS  PubMed  Google Scholar 

  9. Laflamme MA, Myerson D, Saffitz JE, Murry CE. Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res. 2002;90:634–40.

    Article  CAS  PubMed  Google Scholar 

  10. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nadal-Ginard B. Generation of new cardiomyocytes in the adult heart: prospects of myocardial regeneration as an alternative to cardiac transplantation. Revista espanola de cardiologia. 2001;54:543–50.

    Article  CAS  PubMed  Google Scholar 

  12. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, et al. Chimerism of the transplanted heart. N Engl J Med. 2002;346:5–15.

    Article  PubMed  Google Scholar 

  13. Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007;13:970–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mollova M, Bersell K, Walsh S, Savla J, Das LT, Park SY, et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci U S A. 2013;110:1446–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell. 2014;157:565–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dawes GS, Mott JC, Widdicombe JG. The foetal circulation in the lamb. J Physiol. 1954;126:563–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lawrence J, Xiao D, Xue Q, Rejali M, Yang S, Zhang L. Prenatal nicotine exposure increases heart susceptibility to ischemia/reperfusion injury in adult offspring. J Pharmacol Exp Ther. 2008;324:331–41.

    Article  CAS  PubMed  Google Scholar 

  18. Mitchell JA, Van Kainen BR. Effects of alcohol on intrauterine oxygen tension in the rat. Alcohol Clin Exp Res. 1992;16:308–10.

    Article  CAS  PubMed  Google Scholar 

  19. Reynolds JD, Penning DH, Dexter F, Atkins B, Hrdy J, Poduska D, et al. Ethanol increases uterine blood flow and fetal arterial blood oxygen tension in the near-term pregnant ewe. Alcohol. 1996;13:251–6.

    Article  CAS  PubMed  Google Scholar 

  20. Webster WS, Abela D. The effect of hypoxia in development. Birth Defects Res C Embryo Today. 2007;81:215–28.

    Article  CAS  PubMed  Google Scholar 

  21. Fisher DJ, Heymann MA, Rudolph AM. Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. Am J Phys. 1980;238:H399–405.

    CAS  Google Scholar 

  22. Lopaschuk GD, Collins-Nakai RL, Itoi T. Developmental changes in energy substrate use by the heart. Cardiovasc Res. 1992;26:1172–80.

    Article  CAS  PubMed  Google Scholar 

  23. Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Morris DL, Craig JC. Metabolic fate of extracted glucose in normal human myocardium. J Clin Invest. 1985;76:1819–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Investig. 1988;82:2017–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Anderson EJ, Yamazaki H, Neufer PD. Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration. J Biol Chem. 2007;282:31257–66.

    Article  CAS  PubMed  Google Scholar 

  26. Rindler PM, Plafker SM, Szweda LI, Kinter M. High dietary fat selectively increases catalase expression within cardiac mitochondria. J Biol Chem. 2013;288:1979–90.

    Article  CAS  PubMed  Google Scholar 

  27. Seifert EL, Estey C, Xuan JY, Harper ME. Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation. J Biol Chem. 2010;285:5748–58.

    Article  CAS  PubMed  Google Scholar 

  28. Moos PJ, Edes K, Fitzpatrick FA. Inactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins. Proc Natl Acad Sci U S A. 2000;97:9215–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Marnett LJ, Riggins JN, West JD. Endogenous generation of reactive oxidants and electrophiles and their reactions with DNA and protein. J Clin Invest. 2003;111:583–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 2009;361:1475–85.

    Article  CAS  PubMed  Google Scholar 

  31. Elhelaly WM, Lam NT, Hamza M, Xia S, Sadek HA. Redox regulation of heart regeneration: an evolutionary tradeoff. Frontiers In Cell And Developmental Biology. 2016;4:137.

    Article  PubMed  PubMed Central  Google Scholar 

  32. • Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, et al. Hypoxia induces heart regeneration in adult mice. Nature. 2017;541:222–7 Findings from this study suggest that oxygen metabolism is a critical regulator of cardiomyocyte cell cycle.

    Article  CAS  PubMed  Google Scholar 

  33. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.

    Article  CAS  PubMed  Google Scholar 

  34. Prabhakar NR, Semenza GL. Oxygen sensing and homeostasis. Physiology. 2015;30:340–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kaelin WG Jr. The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun. 2005;338:627–38.

    Article  CAS  PubMed  Google Scholar 

  36. Jopling C, Sleep E, Raya M, Marti M, Raya A, Izpisua Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010;464:606–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dunwoodie SL. The role of hypoxia in development of the mammalian embryo. Dev Cell. 2009;17:755–73.

    Article  CAS  PubMed  Google Scholar 

  38. Breckenridge RA, Piotrowska I, Ng KE, Ragan TJ, West JA, Kotecha S, et al. Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. PLoS Biol. 2013;11:e1001666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Guimaraes-Camboa N, Stowe J, Aneas I, Sakabe N, Cattaneo P, Henderson L, et al. HIF1alpha represses cell stress pathways to allow proliferation of hypoxic fetal cardiomyocytes. Dev Cell. 2015;33:507–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Menendez-Montes I, Escobar B, Palacios B, Gomez MJ, Izquierdo-Garcia JL, Flores L, et al. Myocardial VHL-HIF signaling controls an embryonic metabolic switch essential for cardiac maturation. Dev Cell. 2016;39:724–39.

    Article  CAS  PubMed  Google Scholar 

  41. Moslehi J, Minamishima YA, Shi J, Neuberg D, Charytan DM, Padera RF, et al. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation. 2010;122:1004–16.

    Article  CAS  PubMed  Google Scholar 

  42. Lei L, Mason S, Liu D, Huang Y, Marks C, Hickey R, et al. Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. Mol Cell Biol. 2008;28:3790–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tao G, Kahr PC, Morikawa Y, Zhang M, Rahmani M, Heallen TR, et al. Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature. 2016;534:119–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu S, Martin JF. The regulation and function of the Hippo pathway in heart regeneration. Wiley Interdiscip Rev Dev Biol. 2019;8:e335.

    Article  PubMed  CAS  Google Scholar 

  45. Contessotto P, Ellis BW, Jin C, Karlsson NG, Zorlutuna P, Kilcoyne M, et al. Distinct glycosylation in membrane proteins within neonatal versus adult myocardial tissue. Matrix Biol. 2019.

  46. Etchegaray JP, Mostoslavsky R. Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol Cell. 2016;62:695–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–80.

    Article  CAS  PubMed  Google Scholar 

  48. Shikama N, Lutz W, Kretzschmar R, Sauter N, Roth JF, Marino S, et al. Essential function of p300 acetyltransferase activity in heart, lung and small intestine formation. EMBO J. 2003;22:5175–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 2007;21:1790–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Collesi C, Felician G, Secco I, Gutierrez MI, Martelletti E, Ali H, et al. Reversible Notch1 acetylation tunes proliferative signalling in cardiomyocytes. Cardiovasc Res. 2018;114:103–22.

    Article  CAS  PubMed  Google Scholar 

  51. Talman V, Teppo J, Poho P, Movahedi P, Vaikkinen A, Karhu ST, et al. Molecular atlas of postnatal mouse heart development. J Am Heart Assoc. 2018;7:e010378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lalowski MM, Bjork S, Finckenberg P, Soliymani R, Tarkia M, Calza G, et al. Characterizing the key metabolic pathways of the neonatal mouse heart using a quantitative combinatorial omics approach. Front Physiol. 2018;9:365.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Broer S, Broer A. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem J. 2017;474:1935–63.

    Article  CAS  PubMed  Google Scholar 

  54. Neinast M, Murashige D, Arany Z. Branched chain amino acids. Annu Rev Physiol. 2019;81:139–64.

    Article  CAS  PubMed  Google Scholar 

  55. Walsh S, Ponten A, Fleischmann BK, Jovinge S. Cardiomyocyte cell cycle control and growth estimation in vivo--an analysis based on cardiomyocyte nuclei. Cardiovasc Res. 2010;86:365–73.

    Article  CAS  PubMed  Google Scholar 

  56. 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;96:110–8.

    Article  CAS  PubMed  Google Scholar 

  57. Gude N, Muraski J, Rubio M, Kajstura J, Schaefer E, Anversa P, et al. Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res. 2006;99:381–8.

    Article  CAS  PubMed  Google Scholar 

  58. Sdek P, Zhao P, Wang Y, Huang CJ, Ko CY, Butler PC, et al. Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes. J Cell Biol. 2011;194:407–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Azcoitia V, Aracil M, Martinez AC, Torres M. The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol. 2005;280:307–20.

    Article  CAS  PubMed  Google Scholar 

  60. Stankunas K, Shang C, Twu KY, Kao SC, Jenkins NA, Copeland NG, et al. Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. Circ Res. 2008;103:702–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lindgren IM, Drake RR, Chattergoon NN, Thornburg KL. Down-regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes. FASEB J. 2019;33:7417–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Malek Mohammadi M, Kattih B, Grund A, Froese N, Korf-Klingebiel M, Gigina A, et al. The transcription factor GATA4 promotes myocardial regeneration in neonatal mice. EMBO Mol Med. 2017;9:265–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yu W, Huang X, Tian X, Zhang H, He L, Wang Y, et al. GATA4 regulates Fgf16 to promote heart repair after injury. Development. 2016;143:936–49.

    Article  CAS  PubMed  Google Scholar 

  64. Zeisberg EM, Ma Q, Juraszek AL, Moses K, Schwartz RJ, Izumo S, et al. Morphogenesis of the right ventricle requires myocardial expression of Gata4. J Clin Invest. 2005;115:1522–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bisping E, Ikeda S, Kong SW, Tarnavski O, Bodyak N, McMullen JR, et al. Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. Proc Natl Acad Sci U S A. 2006;103:14471–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Oka T, Maillet M, Watt AJ, Schwartz RJ, Aronow BJ, Duncan SA, et al. Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ Res. 2006;98:837–45.

    Article  CAS  PubMed  Google Scholar 

  67. Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010;464:601–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Delgado-Olguin P, Huang Y, Li X, Christodoulou D, Seidman CE, Seidman JG, et al. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet. 2012;44:343–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen L, Ma Y, Kim EY, Yu W, Schwartz RJ, Qian L, et al. Conditional ablation of Ezh2 in murine hearts reveals its essential roles in endocardial cushion formation, cardiomyocyte proliferation and survival. PLoS One. 2012;7:e31005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ahmed A, Wang T, Delgado-Olguin P. Ezh2 is not required for cardiac regeneration in neonatal mice. PLos One. 2018;13:e0192238.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Porrello ER, Olson EN. A neonatal blueprint for cardiac regeneration. Stem Cell Res. 2014;13:556–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev. 2014;94:1287–312.

    Article  CAS  PubMed  Google Scholar 

  73. Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, et al. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal. 2011;4:ra70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. von Gise A, Lin Z, Schlegelmilch K, Honor LB, Pan GM, Buck JN, et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A. 2012;109:2394–9.

    Article  Google Scholar 

  75. Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc Natl Acad Sci U S A. 2013;110:13839–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Del Re DP, Yang Y, Nakano N, Cho J, Zhai P, Yamamoto T, et al. Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury. J Biol Chem. 2013;288:3977–88.

    Article  PubMed  CAS  Google Scholar 

  77. Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell. 2009;16:398–410.

    Article  CAS  PubMed  Google Scholar 

  78. Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332:458–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang J, Liu S, Heallen T, Martin JF. The hippo pathway in the heart: pivotal roles in development, disease, and regeneration. Nat Rev Cardiol. 2018;15:672–84.

    Article  CAS  PubMed  Google Scholar 

  80. Heallen T, Morikawa Y, Leach J, Tao G, Willerson JT, Johnson RL, et al. Hippo signaling impedes adult heart regeneration. Development. 2013;140:4683–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci U S A. 2008;105:2111–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007;129:303–17.

    Article  CAS  PubMed  Google Scholar 

  83. Tatsuguchi M, Seok HY, Callis TE, Thomson JM, Chen JF, Newman M, et al. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2007;42:1137–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Porrello ER, Johnson BA, Aurora AB, Simpson E, Nam YJ, Matkovich SJ, et al. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ Res. 2011;109:670–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tian Y, Liu Y, Wang T, Zhou N, Kong J, Chen L, et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci Transl Med. 2015;7:279ra238.

    Article  CAS  Google Scholar 

  86. Huang W, Feng Y, Liang J, Yu H, Wang C, Wang B, et al. Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration. Nat Commun. 2018;9:700.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495:107–10.

    Article  CAS  PubMed  Google Scholar 

  88. Yang Y, Cheng HW, Qiu Y, Dupee D, Noonan M, Lin YD, et al. MicroRNA-34a plays a key role in cardiac repair and regeneration following myocardial infarction. Circ Res. 2015;117:450–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Eulalio A, Mano M, Dal Ferro M, Zentilin L, Sinagra G, Zacchigna S, et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature. 2012;492:376–81.

    Article  CAS  PubMed  Google Scholar 

  90. •• Gabisonia K, Prosdocimo G, Aquaro GD, Carlucci L, Zentilin L, Secco I, et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. 2019;569:418–22 Findings from this study suggests that heart regeneration through cardiomyocyte proliferation is achievable in large animals, but caution is warranted since widespread cardiomyocyte proliferation can have serious side effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435:839–43.

    Article  PubMed  CAS  Google Scholar 

  93. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132:875–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen J, Huang ZP, Seok HY, Ding J, Kataoka M, Zhang Z, et al. mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. Circ Res. 2013;112:1557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Frangogiannis NG. Inflammation in cardiac injury, repair and regeneration. Curr Opin Cardiol. 2015;30:240–5.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Han C, Nie Y, Lian H, Liu R, He F, Huang H, et al. Acute inflammation stimulates a regenerative response in the neonatal mouse heart. Cell Res. 2015;25:1137–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, et al. Macrophages are required for neonatal heart regeneration. J Clin Invest. 2014;124:1382–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lavine KJ, Epelman S, Uchida K, Weber KJ, Nichols CG, Schilling JD, et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci U S A. 2014;111:16029–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wodsedalek DJ, Paddock SJ, Wan TC, Auchampach JA, Kenarsary A, Tsaih SW, et al. IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration. Am J Physiol Heart Circ Physiol. 2019;316:H24–34.

    Article  CAS  PubMed  Google Scholar 

  100. Bassat E, Mutlak YE, Genzelinakh A, Shadrin IY, Baruch Umansky K, Yifa O, et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature. 2017;547:179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tsen G, Halfter W, Kroger S, Cole GJ. Agrin is a heparan sulfate proteoglycan. J Biol Chem. 1995;270:3392–9.

    Article  CAS  PubMed  Google Scholar 

  102. Notari M, Ventura-Rubio A, Bedford-Guaus SJ, Jorba I, Mulero L, Navajas D, et al. The local microenvironment limits the regenerative potential of the mouse neonatal heart. Sci Adv. 2018;4:eaao5553.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Kumar A, Brockes JP. Nerve dependence in tissue, organ, and appendage regeneration. Trends Neurosci. 2012;35:691–9.

    Article  CAS  PubMed  Google Scholar 

  104. Garikipati VN, Verma SK, Kishore R. The nervous heart: role of sympathetic reinnervation in cardiac regeneration. Circ Res. 2015;117:980–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mahmoud AI, O’Meara CC, Gemberling M, Zhao L, Bryant DM, Zheng R, et al. Nerves regulate cardiomyocyte proliferation and heart regeneration. Dev Cell. 2015;34:387–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. White IA, Gordon J, Balkan W, Hare JM. Sympathetic reinnervation is required for mammalian cardiac regeneration. Circ Res. 2015;117:990–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Vaseghi M, Lux RL, Mahajan A, Shivkumar K. Sympathetic stimulation increases dispersion of repolarization in humans with myocardial infarction. Am J Physiol Heart Circ Physiol. 2012;302:H1838–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mohamed TMA, Ang YS, Radzinsky E, Zhou P, Huang Y, Elfenbein A, et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell. 2018;173(104–116):e112.

    Google Scholar 

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Authors and Affiliations

  1. Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Sao Paulo, Brazil

    Alisson C. Cardoso & Ana Helena M. Pereira

  2. Department of Internal Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX, 75390, USA

    Hesham A. Sadek

  3. Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Hesham A. Sadek

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  1. Alisson C. Cardoso
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  2. Ana Helena M. Pereira
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  3. Hesham A. Sadek
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Correspondence to Hesham A. Sadek.

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Alisson C. Cardoso, Ana Helena M. Pereira, and Hesham A. Sadek declare that they have no conflict of interest.

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Cardoso, A.C., Pereira, A.H.M. & Sadek, H.A. Mechanisms of Neonatal Heart Regeneration. Curr Cardiol Rep 22, 33 (2020). https://doi.org/10.1007/s11886-020-01282-5

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