1887
Volume 2013, Issue 3
  • ISSN: 2305-7823
  • E-ISSN:

Abstract

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Recently, our group demonstrated that neonatal mammalian hearts have a remarkable regenerative potential in the first few days after birth. Although adult mammals lack this regenerative potential, it is now clear that there is measurable cardiomyocyte turnover that occurs in the adult mammalian heart. In both neonatal and adult mammals, proliferation of pre-existing cardiomyocytes appears to be the underlying mechanism of myocyte turnover. This review will highlight the advances and landmark studies that opened new frontiers in cardiac regeneration.

Loading

Article metrics loading...

/content/journals/10.5339/gcsp.2013.29
2014-01-01
2020-02-21
Loading full text...

Full text loading...

/deliver/fulltext/gcsp/2013/3/gcsp.2013.29.html?itemId=/content/journals/10.5339/gcsp.2013.29&mimeType=html&fmt=ahah

References

  1. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003; 348::20072018, doi:10.1056/NEJMra021498 .
    [Google Scholar]
  2. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011; 473::326335, doi:10.1038/nature10147 .
    [Google Scholar]
  3. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA. Transient regenerative potential of the neonatal mouse heart. Science. 2011; 331::10781080, doi:10.1126/science.1200708 .
    [Google Scholar]
  4. Mahmoud AI, Porrello ER. Turning back the cardiac regenerative clock: lessons from the neonate. Trends Cardiovasc Med. 2012; 22::128133, doi:10.1016/j.tcm.2012.07.008 .
    [Google Scholar]
  5. Porrello ER, Mahmoud AI, Simpson E, Johnson BA, Grinsfelder D, Canseco D, Mammen PP, Rothermel BA, Olson EN, Sadek HA. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A. 2013; 110::187192, doi:10.1073/pnas.1208863110 .
    [Google Scholar]
  6. Kroehne V, Freudenreich D, Hans S, Kaslin J, Brand M. Regeneration of the adult zebrafish brain from neurogenic radial glia-type progenitors. Development. 2011; 138::48314841, doi:dev.072587 [pii] 10.1242/dev.072587 .
    [Google Scholar]
  7. Poss KD, Keating MT, Nechiporuk A. Tales of regeneration in zebrafish. Dev Dyn. 2003; 226::202210, doi:10.1002/dvdy.10220 .
    [Google Scholar]
  8. Vihtelic TS, Hyde DR. Light-induced rod and cone cell death and regeneration in the adult albino zebrafish (Danio rerio) retina. J Neurobiol. 2000; 44::289307, doi:10.1002/1097-4695(20000905)44:3 < 289:AID-NEU1>3.0.CO;2-H [pii] .
    [Google Scholar]
  9. Poss KD. Getting to the heart of regeneration in zebrafish. Semin Cell Dev Biol. 2007; 18:1:3645, doi:10.1016/j.semcdb.2006.11.009 .
    [Google Scholar]
  10. Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science. 2002; 298::21882190, doi:10.1126/science.1077857 .
    [Google Scholar]
  11. Jopling C, Sleep E, Raya M, Martí M, Raya A, Izpisúa Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010; 464::606609, doi:10.1038/nature08899 .
    [Google Scholar]
  12. Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, Macrae CA, Stainier DY, Poss KD. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010; 464::601605, doi:10.1038/nature08804 .
    [Google Scholar]
  13. Chablais F, Veit J, Rainer G, Jazwinska A. The zebrafish heart regenerates after cryoinjury-induced myocardial infarction. BMC Dev Biol. 2011; 11::21. doi:1471-213X-11-21 [pii] 10.1186/1471-213X-11-21 .
    [Google Scholar]
  14. Gonzalez-Rosa JM, Martin V, Peralta M, Torres M, Mercader N. Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development. 2011; 138::16631674, doi:10.1242/dev.060897 .
    [Google Scholar]
  15. Jopling C, Sune G, Faucherre A, Fabregat C, Izpisua Belmonte JC. Hypoxia induces myocardial regeneration in zebrafish. Circulation. 2012; 126::30173027, doi:CIRCULATIONAHA.112.107888 [pii] 10.1161/CIRCULATIONAHA.112.107888 .
    [Google Scholar]
  16. Parente V, Balasso S, Pompilio G, Verduci L, Colombo GI, Milano G, Guerrini U, Squadroni L, Cotelli F, Pozzoli O, Capogrossi MC. Hypoxia/reoxygenation cardiac injury and regeneration in zebrafish adult heart. PLoS One. 2013; 8::e53748. doi:10.1371/journal.pone.0053748 PONE-D-12-29126 [pii] .
    [Google Scholar]
  17. Brockes JP, Kumar A. Appendage regeneration in adult vertebrates and implications for regenerative medicine. Science. 2005; 310::19191923, doi:10.1126/science.1115200 .
    [Google Scholar]
  18. Eguchi G. Cellular and molecular background of wolffian lens regeneration. Cell Differ Dev. 1988; 25::147158.
    [Google Scholar]
  19. Ghosh S, Thorogood P, Ferretti P. Regenerative capability of upper and lower jaws in the newt. Int J Dev Biol. 1994; 38::479490.
    [Google Scholar]
  20. Keefe JR. An analysis of urodelian retinal regeneration. IV. Studies of the cellular source of retinal regeneration in Triturus cristatus carnifex using 3 H-thymidine. J Exp Zool. 1973; 184::239258, doi:10.1002/jez.1401840209 .
    [Google Scholar]
  21. Minelli G, Franceschini V, Del Grande P, Ciani F. Newly-formed neurons in the regenerating optic tectum of Triturus cristatus carnifex. Basic Appl Histochem. 1987; 31::4352.
    [Google Scholar]
  22. O'Steen WK, Walker BE. Radioautographic studies or regeneration in the common newt. III. Regeneration and repair of the intestine. Anat Rec. 1962; 142::179187.
    [Google Scholar]
  23. Oberpriller JO, Oberpriller JC. Response of the adult newt ventricle to injury. J Exp Zool. 1974; 187:2:249253, doi:10.1002/jez.1401870208 .
    [Google Scholar]
  24. Flink IL. Cell cycle reentry of ventricular and atrial cardiomyocytes and cells within the epicardium following amputation of the ventricular apex in the axolotl, Amblystoma mexicanum: confocal microscopic immunofluorescent image analysis of bromodeoxyuridine-labeled nuclei. Anat Embryol (Berl). 2002; 205:3:235244, doi:10.1007/s00429-002-0249-6 .
    [Google Scholar]
  25. Witman N, Murtuza B, Davis B, Arner A, Morrison JI. Recapitulation of developmental cardiogenesis governs the morphological and functional regeneration of adult newt hearts following injury. Dev Biol. 2011; 354::6776, doi:S0012-1606(11)00185-0 [pii] 10.1016/j.ydbio.2011.03.021 .
    [Google Scholar]
  26. Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Physiol. 1996; 271::H2183H2189.
    [Google Scholar]
  27. 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::365373, doi:10.1093/cvr/cvq005 .
    [Google Scholar]
  28. Mollova M, Bersell K, Walsh S, Savla J, Das LT, Park SY, Silberstein LE, Dos Remedios CG, Graham D, Colan S, Kühn B. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci U S A. 2013; 110::14461451, doi:10.1073/pnas.1214608110 .
    [Google Scholar]
  29. Michielon G, Di Carlo D, Brancaccio G, Guccione P, Mazzera E, Toscano A, Di Donato RM. Anomalous coronary artery origin from the pulmonary artery: correlation between surgical timing and left ventricular function recovery. Ann Thorac Surg. 2003; 76::581588, discussion 588, doi:S0003497503003448 [pii] .
    [Google Scholar]
  30. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J. Evidence for cardiomyocyte renewal in humans. Science. 2009; 324::98102, doi:10.1126/science.1164680 .
    [Google Scholar]
  31. Bergmann O, Zdunek S, Frisén J, Bernard S, Druid H, Jovinge S. Cardiomyocyte renewal in humans. Circ Res. 2012; 110::e17e18, author reply e19–21, doi:110/1/e17 [pii] 10.1161/CIRCRESAHA.111.259598 .
    [Google Scholar]
  32. Laflamme MA, Myerson D, Saffitz JE, Murry CE. Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res. 2002; 90::634640.
    [Google Scholar]
  33. Nadal-Ginard B. Generation of new cardiomyocytes in the adult heart: prospects of myocardial regeneration as an alternative to cardiac transplantation. Rev Esp Cardiol. 2001; 54::543550.
    [Google Scholar]
  34. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, Kajstura J, Leri A, Anversa P. Chimerism of the transplanted heart. N Engl J Med. 2002; 346::515, doi:10.1056/NEJMoa012081 .
    [Google Scholar]
  35. Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Physiol. 1997; 272::H220H226.
    [Google Scholar]
  36. Soonpaa MH, Field LJ. Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res. 1998; 83::1526.
    [Google Scholar]
  37. Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, Lee RT. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013; 493::433436, doi:nature11682 [pii] 10.1038/nature11682 .
    [Google Scholar]
  38. Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, Sun B, Aminzadeh M, Marbán E. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med. 2013; 5::191209, doi:10.1002/emmm.201201737 .
    [Google Scholar]
  39. Hesse M, Raulf A, Pilz GA, Haberlandt C, Klein AM, Jabs R, Zaehres H, Fügemann CJ, Zimmermann K, Trebicka J, Welz A, Pfeifer A, Röll W, Kotlikoff MI, Steinhäuser C, Götz M, Schöler HR, Fleischmann BK. Direct visualization of cell division using high-resolution imaging of M-phase of the cell cycle. Nat Commun. 2012; 3::1076. doi:10.1038/ncomms2089 .
    [Google Scholar]
  40. Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007; 13::970974, doi:10.1038/nm1618 .
    [Google Scholar]
  41. Rumyantsev PP. Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int Rev Cytol. 1977; 51::186273.
    [Google Scholar]
  42. Pasumarthi KB, Field LJ. Cardiomyocyte cell cycle regulation. Circ Res. 2002; 90::10441054.
    [Google Scholar]
  43. Obaya AJ, Sedivy JM. Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci. 2002; 59::126142.
    [Google Scholar]
  44. Dowell JD, Field LJ, Pasumarthi KB. Cell cycle regulation to repair the infarcted myocardium. Heart Fail Rev. 2003; 8::293303.
    [Google Scholar]
  45. Lafontant PJ, Field LJ. The cardiomyocyte cell cycle. Novartis Found Symp. 2006; 274::196207, discussion 208–113, 272–196.
    [Google Scholar]
  46. Cobrinik D. Pocket proteins and cell cycle control. Oncogene. 2005; 24::27962809, doi:1208619 [pii] 10.1038/sj.onc.1208619 .
    [Google Scholar]
  47. Poolman RA, Li JM, Durand B, Brooks G. Altered expression of cell cycle proteins and prolonged duration of cardiac myocyte hyperplasia in p27KIP1 knockout mice. Circ Res. 1999; 85::117127.
    [Google Scholar]
  48. Poolman RA, Gilchrist R, Brooks G. Cell cycle profiles and expressions of p21CIP1 AND P27KIP1 during myocyte development. Int J Cardiol. 1998; 67::133142.
    [Google Scholar]
  49. Poolman RA, Brooks G. Expressions and activities of cell cycle regulatory molecules during the transition from myocyte hyperplasia to hypertrophy. J Mol Cell Cardiol. 1998; 30::21212135, doi:S0022-2828(98)90808-2 [pii] 10.1006/jmcc.1998.0808 .
    [Google Scholar]
  50. Li JM, Poolman RA, Brooks G. Role of G1 phase cyclins and cyclin-dependent kinases during cardiomyocyte hypertrophic growth in rats. Am J Physiol. 1998; 275::H814H822.
    [Google Scholar]
  51. Brooks G, Poolman RA, McGill CJ, Li JM. Expression and activities of cyclins and cyclin-dependent kinases in developing rat ventricular myocytes. J Mol Cell Cardiol. 29::22612271, doi:S0022-2828(97)90471-5 [pii] 10.1006/jmcc.1997.0471 .
    [Google Scholar]
  52. Brooks G, Poolman RA, Li JM. Arresting developments in the cardiac myocyte cell cycle: role of cyclin-dependent kinase inhibitors. Cardiovasc Res. 1998; 39::301311, doi:S0008636398001254 [pii] .
    [Google Scholar]
  53. Field LJ. Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. Science. 1988; 239::10291033.
    [Google Scholar]
  54. Sen A, Dunnmon P, Henderson SA, Gerard RD, Chien KR. Terminally differentiated neonatal rat myocardial cells proliferate and maintain specific differentiated functions following expression of SV40 large T antigen. J Biol Chem. 1988; 263::1913219136.
    [Google Scholar]
  55. Jackson T, Allard MF, Sreenan CM, Doss LK, Bishop SP, Swain JL. The c-myc proto-oncogene regulates cardiac development in transgenic mice. Mol Cell Biol. 1990; 10::37093716.
    [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::110118, doi:10.1161/01.RES.0000152326.91223.4F .
    [Google Scholar]
  57. Perez-Roger I, Kim SH, Griffiths B, Sewing A, Land H. Cyclins D1 and D2 mediate myc-induced proliferation via sequestration of p27(Kip1) and p21(Cip1). EMBO J. 1999; 18::53105320, doi:10.1093/emboj/18.19.5310 .
    [Google Scholar]
  58. Liao HS, Kang PM, Nagashima H, Yamasaki N, Usheva A, Ding B, Lorell BH, Izumo S. Cardiac-specific overexpression of cyclin-dependent kinase 2 increases smaller mononuclear cardiomyocytes. Circ Res. 2001; 88::443450.
    [Google Scholar]
  59. Soonpaa MH, Koh GY, Pajak L, Jing S, Wang H, Franklin MT, Kim KK, Field LJ. Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice. J Clin Invest. 1997; 99::26442654, doi:10.1172/JCI119453 .
    [Google Scholar]
  60. Agah R, Kirshenbaum LA, Abdellatif M, Truong LD, Chakraborty S, Michael LH, Schneider MD. Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo. J Clin Invest. 1997; 100::27222728, doi:10.1172/JCI119817 .
    [Google Scholar]
  61. Engel FB, Hsieh PC, Lee RT, Keating MT. FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci U S A. 2006; 103::1554615551, doi:10.1073/pnas.0607382103 .
    [Google Scholar]
  62. Kühn B, del Monte F, Hajjar RJ, Chang Y-S, Lebeche D, Arab S, Keating MT. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med. 2007; 13::962969, doi:10.1038/nm1619 .
    [Google Scholar]
  63. Bersell K, Arab S, Haring B, Kuhn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell. 2009; 138::257270, doi:10.1016/j.cell.2009.04.060 .
    [Google Scholar]
  64. Braun T, Dimmeler S. Breaking the silence: stimulating proliferation of adult cardiomyocytes. Dev Cell. 17::151153, doi:S1534-5807(09)00306-2 [pii] 10.1016/j.devcel.2009.07.022 .
    [Google Scholar]
  65. Lorts A, Schwanekamp JA, Elrod JW, Sargent MA, Molkentin JD. Genetic manipulation of periostin expression in the heart does not affect myocyte content, cell cycle activity, or cardiac repair. Circ Res. 2009; 104::e1e7, doi:10.1161/CIRCRESAHA.108.188649 .
    [Google Scholar]
  66. Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011; 332::458461, doi:10.1126/science.1199010 .
    [Google Scholar]
  67. von Gisea A, Lina Z, Schlegelmilchc K, Honora LB, Pana GM, Bucka JN, Maa Q, Ishiwatag T, Zhoua B, Camargoc FD, Pua WT. 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::23942399, doi:10.1073/pnas.1116136109 .
    [Google Scholar]
  68. Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, Richardson JA, Bassel-Duby R, Olson EN. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal. 2011; 4::ra70. doi:10.1126/scisignal.2002278 .
    [Google Scholar]
  69. Mahmoud AI, Kocabas F, Muralidhar SA, Kimura W, Koura AS, Thet S, Porrello ER, Sadek HA. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature. 2013; 497::249253, doi:nature12054 [pii] 10.1038/nature12054 .
    [Google Scholar]
  70. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009; 136::215233, doi:10.1016/j.cell.2009.01.002 .
    [Google Scholar]
  71. Porrello ER. microRNAs in cardiac development and regeneration. Clin Sci (Lond). 2013; 125::151166, doi:10.1042/CS20130011 .
    [Google Scholar]
  72. Porrello ER, Johnson BA, Aurora AB, Simpson E, Nam YJ, Matkovich SJ, Dorn GW 2nd, van Rooij E, Olson EN. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ Res. 2011; 109::670679, doi:10.1161/CIRCRESAHA.111.248880 .
    [Google Scholar]
  73. Hullinger TG, Montgomery RL, Seto AG, Dickinson BA, Semus HM, Lynch JM, Dalby CM, Robinson K, Stack C, Latimer PA, Hare JM, Olson EN, van Rooij E. Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res. 2012; 110::7181, doi:10.1161/CIRCRESAHA.111.244442 .
    [Google Scholar]
  74. Yin VP, Lepilina A, Smith A, Poss KD. Regulation of zebrafish heart regeneration by miR-133. Dev Biol. 2012; 365::319327, doi:10.1016/j.ydbio.2012.02.018 .
    [Google Scholar]
  75. Eulalio A, Mano M, Dal Ferro M, Zentilin L, Sinagra G, Zacchigna S, Giacca M. Functional screening identifies miRNAs inducing cardiac regeneration. Nature. 2012; 492::376381, doi:10.1038/nature11739 .
    [Google Scholar]
  76. Chen J, Huang ZP, Seok HY, Ding J, Kataoka M, Zhang Z, Hu X, Wang G, Lin Z, Wang S, Pu WT, Liao R, Wang DZ. mir-17-92 Cluster is Required for and Sufficient to Induce Cardiomyocyte Proliferation in Postnatal and Adult Hearts. Circ Res. 2013; 112:12:15571566, doi:10.1161/CIRCRESAHA.112.300658 .
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.5339/gcsp.2013.29
Loading
/content/journals/10.5339/gcsp.2013.29
Loading

Data & Media loading...

Supplements

Supplementary File 1

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error