Deten, Alexander

Gorr, Thomas A.

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EditorialManipulating myocyte cell cycle controlfor cardiac repairThomas A. Gorr1 and Alexander Deten2*1Institute for Veterinary Physiology, University of Zurich, Winterthurerstr. 260, 8057 Zurich, Switzerland; and 2FraunhoferInstitute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, GermanyOnline publish-ahead-of-print 8 September 2008This editorial refers to ‘Cardiomyocyte proliferation andprotection against post-myocardial infarction heartfailure by cyclin D1 and Skp2 ubiquitin ligase’ byTamamori-Adachi et al.,11 pp. 181–190, this issue.A fundamental tenet in cardiac biology, namely that the heartis a postmitotic organ incapable of regeneration, has recentlybeen challenged. According to the traditional belief, thenumber of cardiac myocytes we are born with is all we willhave for the rest of our lives. If myocytes die (e.g. as theresult of infarction), they cannot be renewed. This is whymyocardial infarction (MI) and its consequences, such as con-gestive heart failure, continue to be a major cause of deathworldwide despite the considerable therapeutic advancesthat have been made over the past decades.In one attempt to evade this dilemma, cell replacementstrategies are currently being investigated for their thera-peutic potential to restore cardiac function. Indeed, agrowing body of evidence from both basic animal studiesand clinical trials indicates that cell-based strategies usingdifferent stem cell populations such as embryonic stemcells, skeletal myoblasts, haematopoietic stem cells, endo-thelial progenitor cells, and mesenchymal stem cells mightbe promising.1,2 According to these studies, improvementsin clinical symptoms, left-ventricular function, and myocar-dial perfusion are feasible with cell therapy. However, thereis an ongoing controversy about the underlying mechanismsand, particularly, the capability of the different implantedprogenitor cells to transdifferentiate and what the essentialprerequisites for this transdifferentiation might be. Only onunderstanding these mechanisms and, likely, through theappropriate priming and engineering of the cells to beimplanted regeneration by this approach might be achieved.Another approach to induce cardiac regeneration forrepair after injury would be to reverse the terminal differ-entiation, as many mammalian tissues respond to injury byactivating committed progenitor cells or by triggering pro-liferation of differentiated cells that re-enter cell cycle.Although several groups have described the presence of pro-genitor or stem cells that can differentiate into cardiac myo-cytes,3,4 there is still much debate and confusion in the ﬁeldregarding their potential for cardiac myocyte differentiationand myocardial repair.5,6 Limited induction of DNA synthesisin the heart has been described in response to variousstimuli.7,8 Yet, there has been little evidence for cyto-plasmic division or cytokinesis in mammals. In contrast tocardiomyocytes from lower vertebrates, which are wellendowed to divide postnatally,9,10 proliferation ceases inthe perinatal mammalian heart in conjunction with thedownregulation of cyclin-dependent kinase (cdk) activities.Myocytes undergo an additional round of DNA synthesisand nuclear mitosis without cytokinesis (acytokineticmitosis) that leaves the majority of adult cardiac myocytesbinucleated in most species. Beyond this stage of differen-tiation, further increases in cardiac mass are possible onlythrough an increase in cell size or hypertrophy.The report by Tamamori-Adachi et al.11 in the current issueof Cardiovascular Research provides encouraging evidencethat manipulation of positive and negative regulators ofcell cycle control mechanisms successfully promotes cardio-myocyte division and, hence, might yield new strategies forthe treatment of ischaemic heart failure. The study con-tinues previous work12 and shows that adenoviral deliveryof S-phase kinase-associated protein 2 (Skp2), an ubiquitinligase that mediates degradation of the cell cycle inhibitorp27, together with nuclear-targeted cyclin D1 (D1NLS) andCdk4 results in increased proliferation (BrdU-positive cellsand expression of Ki67) and increased mitosis (phosphoryl-ation of histone H3, Aurora B and Survivin) after coronaryartery ligation in rats. Furthermore, gene expression proﬁlingby microarray analysis of rat neonatal cardiomyocytesexpressing D1NLS and Cdk4 in culture showed gene activationfor a subset of G1/S, S phase, G2/M, and M phase check-points, thereby further suggesting the feasibility of profoundand effectivemanipulation of cell cycle control in heart cells.Indeed, the authors demonstrated cytokinesis in cardiomyo-cytes in vivo with daughter cells staining positive for tropo-myosin. To note, cytokinesis is important since in normaladult hearts a number of cardiomyocytes are polyploidand/or multinucleated. Moreover, nuclear hyperplasia andmultinucleation have been associated with cell hypertrophyas mechanism of growth in the postnatal heart. The currentstudy complements the previous attempts to overcome theproliferation arrest in adult cardiomyocytes by manipulationof cell cycle control. In these earlier studies, transgenic miceoverexpressing cyclin D2 showed higher rates of DNA synthesis*Corresponding author. Tel: þ49 341 972 5810; fax: þ49 341 972 5809.E-mail address: alexander.deten@izi.fraunhofer.deThe opinions expressed in this article are not necessarily those of the Editorsof Cardiovascular Research or of the European Society of Cardiology.Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.For permissions please email: journals.permissions@oxfordjournals.org.Cardiovascular Research (2008) 80, 161–162doi:10.1093/cvr/cvn241and signs of mitosis (H3P) or newly formed myocardium afterinfarction,13,14 likely by phosphorylation of cyclin D2-targetretinoblastoma gene product (pRb) being prevented. Accord-ingly, a cyclin D2 knockout prevented the increase in the rela-tive heart weight after transverse aortic constriction.15Furthermore,mice lacking Rband p130 showed signs of persist-ing proliferation of cardiomyocytes during adulthood (BrdU,H3P), along with the expression of c-Myc, E2F, and CycE, andincreased activity of Cdk2, Cdk4, and Cdk6.16 There is alsostrong evidence that inhibition of p38 MAPK in combinationwith FGF1 stimulation, promotes hypertrophy and cytokinesisin adult cardiomyocytes.17,18 Interestingly, inhibition of p38MAPK augments growth factor-mediated induction of allphases of the cell cycle and substantially enhances the prolif-erative capacity of mammalian cardiomyocytes. Additionally,p38 activity prevented upregulation of factors required for kar-yokinesis and cytokinesis, suggesting a role for p38 in G2/Mcheckpoint control. Furthermore, cyclin A2 induced cardio-myocyte mitosis (H3P), increased myocardial proliferation,and improved heart function after MI,19,20 while ectopicexpression of cyclin B1 and Cdk2 induced mitosis-promotingfactor (MPF) activity in adult cardiomyocytes, which resultedin a mitotic phenotype, but no complete cell division.21Taken together, the data in the current study further conﬁrmthat manipulation of cell cycle regulation might offer reason-able strategies for cardiac regeneration and treatment ofischaemic heart failure. The signiﬁcance of the inducedmyocyte proliferation is strengthened by the observed protec-tion against cardiac dysfunction and heart failure in an ischae-mia/reperfusion-induced acute MI model.There are, however, still unanswered questions that needto be addressed. First, the quantitative contribution of theobserved myocyte proliferation per se to the observed pro-tective effects is not clear. Besides technical limitations(assessment and variability of the initial MI size), it is quitepossible that cardio-protective effects (i.e. smaller MI sizeand improved function) are mediated by multiple mechan-isms as stated by the authors. These may include paracrineeffects by induction or suppression of cytokines and growthfactors, resulting in reduced rate of apoptosis and increasedvascularization as also reported in this study. Also, the tem-poral correlation of these angiogenic and anti-apopticeffects to cell proliferation is not completely conclusive.Moreover, the role of other factors contributing to post-ischaemic heart failure (i.e. hypertrophy, remodelling) hasnot been studied, and the occurrence of transient dedifferen-tiation of the myoﬁbrils in the proliferating adult cardiomyo-cytes has not been investigated. It may also be speculatedthat the observed enhanced proliferation occurred inyoung cardiomyocytes simply because the cells derive fromthe (limited) pool of cardiac progenitor cells. If so, thenadditional cell cycle regulators need to be targeted inadult cardiomyocytes for a more substantial onset ofproliferation. Alternatively, this goal may also be achievedby the development of more efﬁcient methods for gene deliv-ery. Finally, the adenoviral delivery for gene transfer alwaysleaves the possibility of a somewhat dysregulated prolifer-ation. As suggested by the authors, this potential problemhas to be considered in a clinical context. Alternativemethods like FGF1 stimulation/p38 MAPK inhibition, perios-tin, or IGF1 are less speciﬁc but more easily adjustable.Although the report by Tamamori-Adachi et al.11 empha-sizes the rationale for continuing research on promotingre-entry of myocytes into the cell cycle for cardiac regener-ation, the fundamental shift in paradigm from the heartbeing strictly a postmitotic organ to one that carries some,although arrested, regenerative capacities clearly has along way to go before such a therapeutic strategy can beapplied in the clinical setting. In addition to taking intoaccount safety considerations, it will be a key prerequisiteto identify the appropriate master regulators of cell cyclecontrol or the most advantageous combinations thereof,which was the aim of the current report.References1. Davani S, Deschaseaux F, Chalmers D, Tiberghien P, Kantelip JP. Can stemcells mend a broken heart? Cardiovasc Res 2005;65:305–316.2. Luttun A, Carmeliet P. De novo vasculogenesis in the heart. CardiovascRes 2003;58:378–389.3. Brockes JP, Kumar A. Appendage regeneration in adult vertebrates andimplications for regenerative medicine. Science 2005;310:1919–1923.4. Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientiﬁcfoundations of cardiac repair. J Clin Invest 2005;115:572–583.5. Anversa P, Leri A, Kajstura J, Nadal-Ginard B. Myocyte growth and cardiacrepair. J Mol Cell Cardiol 2002;34:91–105.6. Rubart M, Field LJ. Cardiac regeneration: repopulating the heart. AnnuRev Physiol 2006;68:29–49.7. Capasso JM, Bruno S, Cheng W, Li P, Rodgers R, Darzynkiewicz Z et al.Ventricular loading is coupled with DNA synthesis in adult cardiac myo-cytes after acute and chronic myocardial infarction in rats. Circ Res1992;71:1379–1389.8. Ferrans VJ, Rodriguez ER. Evidence of myocyte hyperplasia in hyper-trophic cardiomyopathy and other disorders with myocardial hypertro-phy? Z Kardiol 1987;76(Suppl 31):20–25.9. Nag AC, Healy CJ, Cheng M. DNA synthesis and mitosis in adult amphibiancardiac muscle cells in vitro. Science 1979;205:1281–1282.10. Oberpriller JO, Oberpriller JC, Matz DG, Soonpaa MH. Stimulation of pro-liferative events in the adult amphibian cardiac myocyte. Ann N Y AcadSci 1995;752:30–46.11. Tamamori-Adachi M, Takagi H, Hashimoto K, Goto K, Hidaka T,Koshimizu U et al. Cardiomyocyte proliferation and protection againstpost-myocardial infarction heart failure by cyclin D1 and Skp2 ubiquitinligase. Cardiovasc Res 2008;80:181–190.12. Tamamori-Adachi M, Ito H, Sumrejkanchanakij P, Adachi S, Hiroe M,Shimizu M et al. Critical role of cyclin D1 nuclear import in cardiomyocyteproliferation. Circ Res 2003;92:e12–e19.13. Pasumarthi KB, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Tar-geted expression of cyclin D2 results in cardiomyocyte DNA synthesisand infarct regression in transgenic mice. Circ Res 2005;96:110–118.14. Hassink RJ, Pasumarthi KB, Nakajima H, Rubart M, Soonpaa MH, de laRiviere AB et al. Cardiomyocyte cell cycle activation improves cardiacfunction after myocardial infarction. Cardiovasc Res 2008;78:18–25.15. Angelis E, Garcia A, Chan SS, Schenke-Layland K, Ren SX, Goodfellow SJet al. A cyclin D2-Rb pathway regulates cardiac myocyte size and RNApolymerase III after biomechanical stress in adult myocardium. Circ Res2008;102:1222–1229.16. MacLellan WR, Garcia A, Oh H, Frenkel P, Jordan MC, Roos KP et al. Over-lapping roles of pocket proteins in the myocardium are unmasked bygerm line deletion of pp130 plus heart-speciﬁc deletion of Rb. Mol CellBiol 2005;25:2486–2497.17. Engel FB, Schebesta M, Duong MT, Lu G, Ren S, Madwed JB et al. p38 MAPkinase inhibition enables proliferation of adult mammalian cardiomyo-cytes. Genes Dev 2005;19:1175–1187.18. Engel FB, Hsieh PCH, Lee RT, Keating MT. FGF1/p38 MAP kinase inhibitortherapy induces cardiomyocyte mitosis, reduces scarring, and rescuesfunction after myocardial infarction. Proc Natl Acad Sci USA 2006;103:15546–15551.19. Chaudhry HW, Dashoush NH, Tang H, Zhang L, Wang X, Wu EX et al. CyclinA2 mediates cardiomyocyte mitosis in the postmitotic myocardium. J BiolChem 2004;279:35858–35866.20. Cheng RK, Asai T, Tang HY, Dashoush NH, Kara RJ, Costa KD et al. CyclinA2 induces cardiac regeneration after myocardial infarction and preventsheart failure. Circ Res 2007;100:1741–1748.21. Datwyler DA, Magyar JP, Weikert C, Wightman L, Wagner E,Eppenberger HM. Reactivation of the mitosis-promoting factor in postmi-totic cardiomyocytes. Cells Tissues Organs 2003;175:61–71.Editorial162

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