{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:20:09Z","timestamp":1790824809301,"version":"4.1.0"},"reference-count":131,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T00:00:00Z","timestamp":1626652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Unlike some lower vertebrates which can completely regenerate their heart, the human heart is a terminally differentiated organ. Cardiomyocytes lost during cardiac injury and heart failure cannot be replaced due to their limited proliferative capacity. Therefore, cardiac injury generally leads to progressive failure. Here, we summarize the latest progress in research on methods to induce cardiomyocyte cell cycle entry and heart repair through the alteration of cardiomyocyte plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions.<\/jats:p>","DOI":"10.3390\/ijms22147720","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T10:07:37Z","timestamp":1626689257000},"page":"7720","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Induced Cardiomyocyte Proliferation: A Promising Approach to Cure Heart Failure"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2241-3792","authenticated-orcid":false,"given":"Abou Bakr M.","family":"Salama","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, 580 S. Preston St., Rm 122, Louisville, KY 40202, USA"},{"name":"Department of Cardiovascular Medicine, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"},{"name":"Department of Cardiac Surgery, Verona University, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Gebreil","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, 580 S. Preston St., Rm 122, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamer M. A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, 580 S. Preston St., Rm 122, Louisville, KY 40202, USA"},{"name":"Diabetes and Obesity Center, Department of Medicine, Division of Environmental Medicine, Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9PL, UK"},{"name":"Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8883-068X","authenticated-orcid":false,"given":"Riham R. E.","family":"Abouleisa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, 580 S. Preston St., Rm 122, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/circ.102.suppl_4.IV-14","article-title":"Congestive heart failure: Fifty years of progress","volume":"102","author":"Braunwald","year":"2000","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0002-9149(91)90255-J","article-title":"Ventricular enlargement and remodeling following acute myocardial infarction: Mechanisms and management","volume":"68","author":"Braunwald","year":"1991","journal-title":"Am. J. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.healun.2005.05.018","article-title":"Registry of the International Society for Heart and Lung Transplantation: Twenty-second Official Adult Heart Transplant Report\u20142005","volume":"24","author":"Taylor","year":"2005","journal-title":"J. Hear. Lung Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1161\/CIRCULATIONAHA.114.011490","article-title":"Fetal Mammalian Heart Generates a Robust Compensatory Response to Cell Loss","volume":"132","author":"Sturzu","year":"2015","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1073\/pnas.1208863110","article-title":"Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family","volume":"110","author":"Porrello","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1126\/science.1200708","article-title":"Transient Regenerative Potential of the Neonatal Mouse Heart","volume":"331","author":"Porrello","year":"2011","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1016\/j.cell.2015.05.026","article-title":"Dynamics of Cell Generation and Turnover in the Human Heart","volume":"161","author":"Bergmann","year":"2015","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1164680","article-title":"Evidence for Cardiomyocyte Renewal in Humans","volume":"324","author":"Bergmann","year":"2009","journal-title":"Science"},{"key":"ref_9","first-page":"226","article-title":"Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart","volume":"523","author":"Kimura","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_10","first-page":"433","article-title":"Mammalian heart renewal by pre-existing cardiomyocytes","volume":"493","author":"Senyo","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1056\/NEJM200106073442303","article-title":"Evidence That Human Cardiac Myocytes Divide after Myocardial Infarction","volume":"344","author":"Beltrami","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1093\/cvr\/cvm101","article-title":"Cardiomyocyte cell cycle activation improves cardiac function after myocardial infarction","volume":"78","author":"Hassink","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1161\/01.RES.0000152326.91223.4F","article-title":"Targeted Expression of Cyclin D2 Results in Cardiomyocyte DNA Synthesis and Infarct Regression in Transgenic Mice","volume":"96","author":"Pasumarthi","year":"2005","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"H220","DOI":"10.1152\/ajpheart.1997.272.1.H220","article-title":"Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts","volume":"272","author":"Soonpaa","year":"1997","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhu, F., Meng, Q., Yu, Y., Shao, L., and Shen, Z. (2020). Adult Cardiomyocyte Proliferation: A New Insight for Myocardial Infarction Therapy. J. Cardiovasc. Transl. Res.","DOI":"10.1007\/s12265-020-10067-8"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1111\/j.1440-169X.2012.01373.x","article-title":"Cell cycle regulation in mouse heart during embryonic and postnatal stages","volume":"54","author":"Ikenishi","year":"2012","journal-title":"Dev. Growth Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S1016-8478(23)13306-1","article-title":"Cyelins and Cyelin Dependent Kinases during Cardiac Development","volume":"7","author":"Kang","year":"1997","journal-title":"Mol. Cells"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.bbrc.2013.12.109","article-title":"CDK inhibitors, p21Cip1 and p27Kip1, participate in cell cycle exit of mammalian cardiomyocytes","volume":"443","author":"Tane","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.bbrc.2015.08.102","article-title":"Two inhibitory systems and CKIs regulate cell cycle exit of mammalian cardiomyocytes after birth","volume":"466","author":"Tane","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1128\/MCB.23.2.555-565.2003","article-title":"p21 CIP1 Controls Proliferating Cell Nuclear Antigen Level in Adult Cardiomyocytes","volume":"23","author":"Engel","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1203\/00006450-199905010-00004","article-title":"p57Kip2 Expression Is Enhanced During Mid-Cardiac Murine Development and Is Restricted to Trabecular Myocardium","volume":"45","author":"Kochilas","year":"1999","journal-title":"Pediatric Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1083\/jcb.201510091","article-title":"Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation","volume":"213","author":"Aix","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8644","DOI":"10.1074\/jbc.M110.184549","article-title":"Knockdown of Cyclin-dependent Kinase Inhibitors Induces Cardiomyocyte Re-entry in the Cell Cycle","volume":"286","author":"Giacca","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1101\/gad.1306705","article-title":"p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes","volume":"19","author":"Engel","year":"2005","journal-title":"Genes Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15992","DOI":"10.1074\/jbc.M107340200","article-title":"Mitogen-activated Protein Kinases and Activator Protein 1 Are Required for Proliferation and Cardiomyocyte Differentiation of P19 Embryonal Carcinoma Cells","volume":"277","author":"Eriksson","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1172\/JCI119453","article-title":"Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice","volume":"99","author":"Soonpaa","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1161\/CIRCRESAHA.109.211888","article-title":"Regulation of cardiomyocyte polyploidy and multinucleation by CyclinG1","volume":"106","author":"Liu","year":"2010","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18033","DOI":"10.1074\/jbc.M113.541953","article-title":"Repression of Cyclin D1 Expression Is Necessary for the Maintenance of Cell Cycle Exit in Adult Mammalian Cardiomyocytes","volume":"289","author":"Tane","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"35858","DOI":"10.1074\/jbc.M404975200","article-title":"Cyclin A2 Mediates Cardiomyocyte Mitosis in the Postmitotic Myocardium","volume":"279","author":"Chaudhry","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"I-206","DOI":"10.1161\/CIRCULATIONAHA.105.000455","article-title":"Therapeutic Delivery of Cyclin A2 Induces Myocardial Regeneration and Enhances Cardiac Function in Ischemic Heart Failure","volume":"114","author":"Woo","year":"2006","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1161\/CIRCRESAHA.107.153544","article-title":"Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction and Prevents Heart Failure","volume":"100","author":"Cheng","year":"2007","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"224ra27","DOI":"10.1126\/scitranslmed.3007668","article-title":"Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction Through Cytokinesis of Adult Cardiomyocytes","volume":"6","author":"Shapiro","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_33","first-page":"e12","article-title":"Critical Role of Cyclin D1 Nuclear Import in Cardiomyocyte Proliferation","volume":"92","author":"Ito","year":"2003","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1042\/BJ20031481","article-title":"Forced expression of the cyclin B1\u2013CDC2 complex induces proliferation in adult rat cardiomyocytes","volume":"382","author":"Katrina","year":"2004","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cell.2018.02.014","article-title":"Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration","volume":"173","author":"Mohamed","year":"2018","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Abouleisa, R., Ou, Q., Tang, X., Solanki, M., Guo, Y., McNally, L., Lorkiewicz, P., Choudhary, K., Thomas, R., and Juhardeen, H.R. (2020). Transient Cell Cycle Induction in Cardiomyocytes to Treat. Ischemic Heart Failure, Research Square.","DOI":"10.21203\/rs.3.rs-122026\/v1"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12546","DOI":"10.18632\/aging.102587","article-title":"Sirt1-inducible deacetylation of p21 promotes cardiomyocyte proliferation","volume":"11","author":"Li","year":"2019","journal-title":"Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4709","DOI":"10.1038\/sj.emboj.7600481","article-title":"The E2F family: Specific functions and overlapping interests","volume":"23","author":"Attwooll","year":"2004","journal-title":"EMBO J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/cvr\/cvn194","article-title":"E2F2 expression induces proliferation of terminally differentiated cardiomyocytes in vivo","volume":"80","author":"Ebelt","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1093\/cvr\/cvp383","article-title":"E2F4 is required for cardiomyocyte proliferation","volume":"86","author":"Diehl","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1083\/jcb.201012049","article-title":"Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes","volume":"194","author":"Sdek","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1128\/MCB.25.6.2486-2497.2005","article-title":"Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb","volume":"25","author":"MacLellan","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1172\/JCI119817","article-title":"Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo","volume":"100","author":"Agah","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1161\/CIRCRESAHA.107.164731","article-title":"The Cell Cycle Factor E2F-1 Activates Bnip3 and the Intrinsic Death Pathway in Ventricular Myocytes","volume":"102","author":"Yurkova","year":"2008","journal-title":"Circ. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ydbio.2005.01.004","article-title":"The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo","volume":"280","author":"Azcoitia","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/nature08899","article-title":"Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation","volume":"464","author":"Jopling","year":"2010","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/sj.emboj.7600038","article-title":"Hematopoietic, angiogenic and eye defects in Meis1 mutant animals","volume":"23","author":"Hisa","year":"2004","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1046\/j.1365-2141.2002.03803.x","article-title":"Frequent co-expression of HoxA9 and Meis1 genes in infant acute lymphoblastic leukaemia with MLL rearrangement","volume":"119","author":"Imamura","year":"2002","journal-title":"Br. J. Haematol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.cell.2012.08.027","article-title":"A Temporal Chromatin Signature in Human Embryonic Stem Cells Identifies Regulators of Cardiac Development","volume":"151","author":"Paige","year":"2012","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.cell.2012.07.035","article-title":"Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage","volume":"151","author":"Wamstad","year":"2012","journal-title":"Cell"},{"key":"ref_51","first-page":"249","article-title":"Meis1 regulates postnatal cardiomyocyte cell cycle arrest","volume":"497","author":"Mahmoud","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/dvdy.10480","article-title":"T-box genes in early embryogenesis","volume":"229","author":"Showell","year":"2004","journal-title":"Dev. Dyn."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/cvr\/cvr112","article-title":"Mechanisms of T-box gene function in the developing heart","volume":"91","author":"Greulich","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1161\/CIRCULATIONAHA.115.019357","article-title":"Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction","volume":"133","author":"Xiang","year":"2016","journal-title":"Circulation"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.yjmcc.2013.05.018","article-title":"Tbx20 promotes cardiomyocyte proliferation and persistence of fetal characteristics in adult mouse hearts","volume":"62","author":"Chakraborty","year":"2013","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4640","DOI":"10.1172\/JCI59472","article-title":"Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function","volume":"121","author":"Shen","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7096","DOI":"10.1128\/MCB.19.10.7096","article-title":"Bone Morphogenetic Proteins Induce Cardiomyocyte Differentiation through the Mitogen-Activated Protein Kinase Kinase Kinase TAK1 and Cardiac Transcription Factors Csx\/Nkx-2.5 and GATA-4","volume":"19","author":"Monzen","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1101\/gad.11.8.1061","article-title":"Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis","volume":"11","author":"Molkentin","year":"1997","journal-title":"Genes Dev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"265","DOI":"10.15252\/emmm.201606602","article-title":"The transcription factor GATA 4 promotes myocardial regeneration in neonatal mice","volume":"9","author":"Mohammadi","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_60","first-page":"271","article-title":"A calcineurin\u2013Hoxb13 axis regulates growth mode of mammalian cardiomyocytes","volume":"582","author":"Nguyen","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1016\/j.jacc.2016.09.945","article-title":"MicroRNAs in Cardiovascular Disease","volume":"68","author":"Barwari","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"279ra38","DOI":"10.1126\/scitranslmed.3010841","article-title":"A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice","volume":"7","author":"Tian","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_63","first-page":"376","article-title":"Functional screening identifies miRNAs inducing cardiac regeneration","volume":"492","author":"Eulalio","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/s41586-019-1191-6","article-title":"MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs","volume":"569","author":"Gabisonia","year":"2019","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/s41467-018-03019-z","article-title":"Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration","volume":"9","author":"Huang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/CIRCRESAHA.118.314223","article-title":"Transient Introduction of miR-294 in the Heart Promotes Cardiomyocyte Cell Cycle Reentry After Injury","volume":"125","author":"Borden","year":"2019","journal-title":"Circ. Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Li, X., Wang, J., Jia, Z., Cui, Q., Zhang, C., Wang, W., Chen, P., Ma, K., and Zhou, C. (2013). MiR-499 Regulates Cell Proliferation and Apoptosis during Late-Stage Cardiac Differentiation via Sox6 and Cyclin D1. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074504"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6609","DOI":"10.1128\/MCB.00398-08","article-title":"Embryonic Stem Cell-Specific miR302-367 Cluster: Human Gene Structure and Functional Characterization of Its Core Promoter","volume":"28","author":"Melen","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.jacc.2013.11.053","article-title":"The Global Health and Economic Burden of Hospitalizations for Heart Failure","volume":"63","author":"Ambrosy","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cr.2018.11.002","article-title":"Molecular switch model for cardiomyocyte proliferation","volume":"8","author":"Hashmi","year":"2019","journal-title":"Cell Regen."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.tibs.2004.03.006","article-title":"Advances in protein kinase B signalling: AKTion on multiple fronts","volume":"29","author":"Brazil","year":"2004","journal-title":"Trends Biochem. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1242\/jcs.009530","article-title":"Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis","volume":"121","author":"Maddika","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.etp.2009.11.005","article-title":"Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt\/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells","volume":"63","author":"Parekh","year":"2011","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1161\/CIRCRESAHA.113.301075","article-title":"C3orf58, a Novel Paracrine Protein, Stimulates Cardiomyocyte Cell-Cycle Progression Through the PI3K\u2013AKT\u2013CDK7 Pathway","volume":"113","author":"Beigi","year":"2013","journal-title":"Circ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1161\/CIRCRESAHA.115.304457","article-title":"Pi3kcbLinks Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival","volume":"116","author":"Lin","year":"2015","journal-title":"Circ. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1161\/01.RES.0000236754.21499.1c","article-title":"Akt Promotes Increased Cardiomyocyte Cycling and Expansion of the Cardiac Progenitor Cell Population","volume":"99","author":"Gude","year":"2006","journal-title":"Circ. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1152\/physrev.00024.2010","article-title":"Myocardial AKT: The Omnipresent Nexus","volume":"91","author":"Sussman","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1073\/pnas.1116136109","article-title":"YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy","volume":"109","author":"Lin","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"ra70","DOI":"10.1126\/scisignal.2002278","article-title":"Regulation of Insulin-Like Growth Factor Signaling by Yap Governs Cardiomyocyte Proliferation and Embryonic Heart Size","volume":"4","author":"Xin","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Gr\u00fcndl, M., Walz, S., Hauf, L., Schwab, M., Werner, K.M., Spahr, S., Schulte, C., Maric, H.M., Ade, C.P., and Gaubatz, S. (2020). Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008818"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.devcel.2019.01.017","article-title":"YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo","volume":"48","author":"Monroe","year":"2019","journal-title":"Dev. Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"13839","DOI":"10.1073\/pnas.1313192110","article-title":"Hippo pathway effector Yap promotes cardiac regeneration","volume":"110","author":"Xin","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1161\/CIRCRESAHA.115.303632","article-title":"Cardiac-Specific YAP Activation Improves Cardiac Function and Survival in an Experimental Murine MI Model","volume":"115","author":"Lin","year":"2014","journal-title":"Circ. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.devcel.2006.12.011","article-title":"Notch Signaling Is Essential for Ventricular Chamber Development","volume":"12","author":"Zurita","year":"2007","journal-title":"Dev. Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1242\/dev.01094","article-title":"BMP10 is essential for maintaining cardiac growth during murine cardiogenesis","volume":"131","author":"Chen","year":"2004","journal-title":"Development"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1073\/pnas.1311705111","article-title":"Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration","volume":"111","author":"Zhao","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1161\/CIRCRESAHA.107.164749","article-title":"Activation of Notch-Mediated Protective Signaling in the Myocardium","volume":"102","author":"Gude","year":"2008","journal-title":"Circ. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1161\/CIRCRESAHA.110.223768","article-title":"WNT Signaling in Adult Cardiac Hypertrophy and Remodeling","volume":"107","author":"Bergmann","year":"2010","journal-title":"Circ. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/ncb1811","article-title":"Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction","volume":"11","author":"Kobayashi","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.chembiol.2006.08.004","article-title":"The GSK-3 Inhibitor BIO Promotes Proliferation in Mammalian Cardiomyocytes","volume":"13","author":"Tseng","year":"2006","journal-title":"Chem. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1172\/JCI36245","article-title":"Deletion of GSK-3\u03b2 in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation","volume":"118","author":"Kerkela","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"13416","DOI":"10.1073\/pnas.1309810110","article-title":"Translational profiling of cardiomyocytes identifies an early Jak1\/Stat3 injury response required for zebrafish heart regeneration","volume":"110","author":"Fang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/s41598-017-01426-8","article-title":"Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis","volume":"7","author":"Miyawaki","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1007\/s00018-017-2534-9","article-title":"Hh signaling in regeneration of the ischemic heart","volume":"74","author":"Dunaeva","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.ydbio.2009.03.028","article-title":"Sonic hedgehog maintains proliferation in secondary heart field progenitors and is required for normal arterial pole formation","volume":"330","author":"Dyer","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1242\/dev.088526","article-title":"In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration","volume":"140","author":"Choi","year":"2013","journal-title":"Development"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature14325","article-title":"Epicardial regeneration is guided by cardiac outflow tract and Hedgehog signalling","volume":"522","author":"Wang","year":"2015","journal-title":"Nature"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"20451","DOI":"10.1161\/circ.130.suppl_2.20451","article-title":"Abstract 20451: Hedgehog Signaling and Cardiomyocyte Proliferation","volume":"130","author":"Singh","year":"2014","journal-title":"Circulation"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/nm1313","article-title":"Sonic hedgehog myocardial gene therapy: Tissue repair through transient reconstitution of embryonic signaling","volume":"11","author":"Kusano","year":"2005","journal-title":"Nat. Med."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Johnson, N.R., and Wang, Y. (2013). Controlled Delivery of Sonic Hedgehog Morphogen and Its Potential for Cardiac Repair. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063075"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"7983","DOI":"10.1038\/srep07983","article-title":"Activation of Sonic hedgehog signaling in ventricular cardiomyocytes exerts cardioprotection against ischemia reperfusion injuries","volume":"5","author":"Paulis","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.1038\/s41467-018-06617-z","article-title":"A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human","volume":"9","author":"Singh","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1161\/CIRCRESAHA.115.307465","article-title":"Sympathetic Reinnervation Is Required for Mammalian Cardiac Regeneration","volume":"117","author":"White","year":"2015","journal-title":"Circ. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"eaaw6419","DOI":"10.1126\/scitranslmed.aaw6419","article-title":"Control of cytokinesis by \u03b2-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment","volume":"11","author":"Liu","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.devcel.2015.06.017","article-title":"Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration","volume":"34","author":"Mahmoud","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_106","first-page":"222","article-title":"Hypoxia induces heart regeneration in adult mice","volume":"541","author":"Nakada","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.devcel.2015.04.021","article-title":"HIF1\u03b1 Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes","volume":"33","author":"Stowe","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1097\/FJC.0b013e3181e74a14","article-title":"Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation","volume":"56","author":"Lopaschuk","year":"2010","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s42255-020-0169-x","article-title":"Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression","volume":"2","author":"Cardoso","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1161\/CIRCULATIONAHA.119.043067","article-title":"Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration","volume":"141","author":"Magadum","year":"2020","journal-title":"Circulation"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Hauck, L., Dadson, K., Chauhan, S., Grothe, D., and Billia, F. (2020). Inhibiting the Pkm2\/b-catenin axis drives in vivo replication of adult cardiomyocytes following experimental MI. Cell Death Differ.","DOI":"10.1038\/s41418-020-00669-9"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1080\/15384101.2015.1063292","article-title":"The key roles of ERBB2 in cardiac regeneration","volume":"14","author":"Tzahor","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"8","DOI":"10.7554\/eLife.50163","article-title":"Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart","volume":"8","author":"Honkoop","year":"2019","journal-title":"eLife"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1161\/CIRCULATIONAHA.120.049952","article-title":"Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration","volume":"143","author":"Bae","year":"2021","journal-title":"Circulation"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.stem.2019.03.009","article-title":"Drug Screening in Human PSC-Cardiac Organoids Identifies Pro-proliferative Compounds Acting via the Mevalonate Pathway","volume":"24","author":"Mills","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.clinbiochem.2007.03.016","article-title":"Mevalonate pathway: A review of clinical and therapeutical implications","volume":"40","author":"Buhaescu","year":"2007","journal-title":"Clin. Biochem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1161\/CIRCRESAHA.119.315408","article-title":"Polyploidy in Cardiomyocytes: Roadblock to Heart Regeneration?","volume":"126","author":"Derks","year":"2020","journal-title":"Circ. Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1093\/cvr\/cvy056","article-title":"Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression","volume":"114","author":"Leone","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.yjmcc.2019.07.005","article-title":"Pseudo-bipolar spindle formation and cell division in postnatal binucleated cardiomyocytes","volume":"134","author":"Leone","year":"2019","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1042\/CS20180560","article-title":"Advances in heart regeneration based on cardiomyocyte proliferation and regenerative potential of binucleated cardiomyocytes and polyploidization","volume":"133","author":"Leone","year":"2019","journal-title":"Clin. Sci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.cell.2005.02.012","article-title":"Mosaic analysis with double markers in mice","volume":"121","author":"Zong","year":"2005","journal-title":"Cell"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"8850","DOI":"10.1073\/pnas.1408233111","article-title":"Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice","volume":"111","author":"Ali","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1161\/CIRCRESAHA.118.312792","article-title":"Midbody Positioning and Distance Between Daughter Nuclei Enable Unequivocal Identification of Cardiomyocyte Cell Division in Mice","volume":"123","author":"Hesse","year":"2018","journal-title":"Circ. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.cell.2007.12.033","article-title":"Visualizing Spatiotemporal Dynamics of Multicellular Cell-Cycle Progression","volume":"132","author":"Kurokawa","year":"2008","journal-title":"Cell"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/cr.2017.84","article-title":"Live cell screening platform identifies PPAR\u03b4 as a regulator of cardiomyocyte proliferation and cardiac repair","volume":"27","author":"Magadum","year":"2017","journal-title":"Cell Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.yjmcc.2018.12.007","article-title":"Cardiomyocyte cell cycle dynamics and proliferation revealed through cardiac-specific transgenesis of fluorescent ubiquitinated cell cycle indicator (FUCCI)","volume":"127","author":"Jr","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"dev164194","DOI":"10.1242\/dev.164194","article-title":"In vivo analysis of cardiomyocyte proliferation during trabeculation","volume":"145","author":"Uribe","year":"2018","journal-title":"Development"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1002\/bit.27352","article-title":"Fluorescent indicators for continuous and lineage-specific reporting of cell-cycle phases in human pluripotent stem cells","volume":"117","author":"Chang","year":"2020","journal-title":"Biotechnol. Bioeng."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1161\/CIRCRESAHA.120.318277","article-title":"Loss of Endogenously Cycling Adult Cardiomyocytes Worsens Myocardial Function","volume":"128","author":"Bradley","year":"2021","journal-title":"Circ. Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1161\/CIRCULATIONAHA.116.024307","article-title":"Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury","volume":"136","author":"Wang","year":"2017","journal-title":"Circulation"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1152\/japplphysiol.00374.2015","article-title":"Myocardial hypertrophy and its role in heart failure with preserved ejection fraction","volume":"119","author":"Heinzel","year":"2015","journal-title":"J. Appl. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7720\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:31:53Z","timestamp":1760164313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7720"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,19]]},"references-count":131,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147720"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147720","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,19]]}}}