{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:56:09Z","timestamp":1790909769459,"version":"4.1.0"},"reference-count":50,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T00:00:00Z","timestamp":1584057600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T00:00:00Z","timestamp":1584057600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T00:00:00Z","timestamp":1584057600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL070123"],"award-info":[{"award-number":["HL070123"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17SDG33400141"],"award-info":[{"award-number":["17SDG33400141"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["OIA-1655740"],"award-info":[{"award-number":["OIA-1655740"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Injury to the newborn mouse heart is efficiently regenerated, but this capacity is lost by one week after birth. We found that IGF2, an important mitogen in heart development, is required for neonatal heart regeneration. IGF2 originates from the endocardium\/endothelium and is transduced in cardiomyocytes by the insulin receptor. Following injury on postnatal day 1, absence of IGF2 abolished injury-induced cell cycle entry during the early part of the first postnatal week. Consequently, regeneration failed despite the later presence of additional cell cycle-inducing activities 7 days following injury. Most cardiomyocytes transition from mononuclear diploid to polyploid during the first postnatal week. Regeneration was rescued in Igf2-deficient neonates in three different contexts that elevate the percentage of mononuclear diploid cardiomyocytes beyond postnatal day 7. Thus, IGF2 is a paracrine-acting mitogen for heart regeneration during the early postnatal period, and IGF2-deficiency unmasks the dependence of this process on proliferation-competent mononuclear diploid cardiomyocytes.<\/jats:p>","DOI":"10.7554\/elife.53071","type":"journal-article","created":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T09:00:31Z","timestamp":1584090031000},"source":"Crossref","is-referenced-by-count":50,"title":["Mononuclear diploid cardiomyocytes support neonatal mouse heart regeneration in response to paracrine IGF2 signaling"],"prefix":"10.7554","volume":"9","author":[{"given":"Hua","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiheng","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, United States"},{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States"},{"name":"Department of Medicine Division of Cardiology, Medical University of South Carolina, Charleston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Darehzereshki","sequence":"additional","affiliation":[{"name":"Saban Research Institute, Children\u2019s Hospital Los Angeles, Los Angeles, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S Ram","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5100-9780","authenticated-orcid":true,"given":"Ching-Ling","family":"Lien","sequence":"additional","affiliation":[{"name":"Saban Research Institute, Children\u2019s Hospital Los Angeles, Los Angeles, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3805-4181","authenticated-orcid":true,"given":"Michaela","family":"Patterson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy, and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3792-3795","authenticated-orcid":true,"given":"Henry M","family":"Sucov","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States"},{"name":"Department of Medicine Division of Cardiology, Medical University of South Carolina, Charleston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,3,13]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1172\/JCI119509","article-title":"Gene recombination in postmitotic cells targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo","volume":"100","author":"Agah","year":"1997","journal-title":"Journal of Clinical Investigation"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/j.cell.2015.10.035","article-title":"No evidence for cardiomyocyte number expansion in preadolescent mice","volume":"163","author":"Alkass","year":"2015","journal-title":"Cell"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.yjmcc.2015.11.031","article-title":"Persistent scarring and dilated cardiomyopathy suggest incomplete regeneration of the apex resected neonatal mouse myocardium--A 180 days follow up study","volume":"90","author":"Andersen","year":"2016","journal-title":"Journal of Molecular and Cellular Cardiology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nature22978","article-title":"The extracellular matrix protein agrin promotes heart regeneration in mice","volume":"547","author":"Bassat","year":"2017","journal-title":"Nature"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/0045-6039(85)90485-3","article-title":"Genome multiplication in cardiomyocytes of fast- and slow-growing mice","volume":"17","author":"Brodsky","year":"1985","journal-title":"Cell Differentiation"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.yjmcc.2014.12.011","article-title":"A systematic analysis of neonatal mouse heart regeneration after apical resection","volume":"79","author":"Bryant","year":"2015","journal-title":"Journal of Molecular and Cellular Cardiology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/nature06969","article-title":"A myocardial lineage derives from Tbx18 epicardial cells","volume":"454","author":"Cai","year":"2008","journal-title":"Nature"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.devcel.2015.03.018","article-title":"CXCL12 signaling is essential for maturation of the ventricular coronary endothelial plexus and establishment of functional coronary circulation","volume":"33","author":"Cavallero","year":"2015","journal-title":"Developmental Cell"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1006\/dbio.2002.0796","article-title":"Epicardial induction of fetal cardiomyocyte proliferation via a retinoic acid-inducible trophic factor","volume":"250","author":"Chen","year":"2002","journal-title":"Developmental Biology"},{"key":"bib10","doi-asserted-by":"publisher","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":"bib11","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1016\/j.cell.2018.12.023","article-title":"A unique collateral artery development program promotes neonatal heart regeneration","volume":"176","author":"Das","year":"2019","journal-title":"Cell"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.devcel.2008.09.005","article-title":"Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development","volume":"15","author":"Drenckhahn","year":"2008","journal-title":"Developmental Cell"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1242\/dev.132910","article-title":"Building and re-building the heart by cardiomyocyte proliferation","volume":"143","author":"Foglia","year":"2016","journal-title":"Development"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"3278","DOI":"10.1128\/MCB.19.5.3278","article-title":"Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells","volume":"19","author":"Frasca","year":"1999","journal-title":"Molecular and Cellular Biology"},{"key":"bib15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008354","article-title":"Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency","volume":"15","author":"Gan","year":"2019","journal-title":"PLOS Genetics"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev-physiol-021119-034618","article-title":"Cardiomyocyte polyploidy and implications for heart regeneration","volume":"82","author":"Gan","year":"2020","journal-title":"Annual Review of Physiology"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.devcel.2018.01.021","article-title":"Myocardial polyploidization creates a barrier to heart regeneration in zebrafish","volume":"44","author":"Gonz\u00e1lez-Rosa","year":"2018","journal-title":"Developmental Cell"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1002\/emmm.201101105","article-title":"Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes","volume":"4","author":"Haley","year":"2012","journal-title":"EMBO Molecular Medicine"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1161\/CIRCRESAHA.115.307017","article-title":"Functional recovery of a human neonatal heart after severe myocardial infarction","volume":"118","author":"Haubner","year":"2016","journal-title":"Circulation Research"},{"key":"bib20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0067266","article-title":"Igf signaling is required for cardiomyocyte proliferation during zebrafish heart development and regeneration","volume":"8","author":"Huang","year":"2013","journal-title":"PLOS ONE"},{"key":"bib21","doi-asserted-by":"publisher","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":"Development, Growth & Differentiation"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.yjmcc.2018.09.005","article-title":"Sonic hedgehog signaling regulates the mammalian cardiac regenerative response","volume":"123","author":"Kawagishi","year":"2018","journal-title":"Journal of Molecular and Cellular Cardiology"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1006\/dbio.2000.0106","article-title":"Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo","volume":"230","author":"Kisanuki","year":"2001","journal-title":"Developmental Biology"},{"key":"bib24","doi-asserted-by":"publisher","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":"Cardiovascular Research"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1242\/dev.054338","article-title":"IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development","volume":"138","author":"Li","year":"2011","journal-title":"Development"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1161\/CIRCRESAHA.119.315280","article-title":"Genetic tracing identifies early segregation of the cardiomyocyte and nonmyocyte lineages","volume":"125","author":"Li","year":"2019","journal-title":"Circulation Research"},{"key":"bib27","doi-asserted-by":"publisher","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":"Developmental Cell"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"2817","DOI":"10.1161\/CIRCULATIONAHA.118.037333","article-title":"Upsizing neonatal heart regeneration","volume":"138","author":"Mahmoud","year":"2018","journal-title":"Circulation"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1002\/emmm.201201737","article-title":"Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart","volume":"5","author":"Malliaras","year":"2013","journal-title":"EMBO Molecular Medicine"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1002\/gene.10022","article-title":"Embryonic expression of an Nkx2-5\/Cre gene using ROSA26 reporter mice","volume":"31","author":"Moses","year":"2001","journal-title":"Genesis"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aao5553","article-title":"The local microenvironment limits the regenerative potential of the mouse neonatal heart","volume":"4","author":"Notari","year":"2018","journal-title":"Science Advances"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"39684","DOI":"10.1074\/jbc.M202766200","article-title":"Insulin\/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved","volume":"277","author":"Pandini","year":"2002","journal-title":"Journal of Biological Chemistry"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1038\/ng.3929","article-title":"Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration","volume":"49","author":"Patterson","year":"2017","journal-title":"Nature Genetics"},{"key":"bib34","doi-asserted-by":"publisher","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":"bib35","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.cell.2014.03.032","article-title":"The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response","volume":"157","author":"Puente","year":"2014","journal-title":"Cell"},{"key":"bib36","first-page":"1215","article-title":"Myocardial regeneration in young rats","volume":"32","author":"Robledo","year":"1956","journal-title":"The American Journal of Pathology"},{"key":"bib37","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.06.009","article-title":"Multi-investigator letter on reproducibility of neonatal heart regeneration following apical resection","volume":"3","author":"Sadek","year":"2014","journal-title":"Stem Cell Reports"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1002\/jcb.1196","article-title":"Regulation of the Akt\/glycogen synthase kinase-3 axis by insulin-like growth factor-II via activation of the human insulin receptor isoform-A","volume":"82","author":"Scalia","year":"2001","journal-title":"Journal of Cellular Biochemistry"},{"key":"bib39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02891-z","article-title":"Analysis of cardiomyocyte clonal expansion during mouse heart development and injury","volume":"9","author":"Sereti","year":"2018","journal-title":"Nature Communications"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1093\/cvr\/cvu269","article-title":"Extracardiac control of embryonic cardiomyocyte proliferation and ventricular wall expansion","volume":"105","author":"Shen","year":"2015","journal-title":"Cardiovascular Research"},{"key":"bib41","doi-asserted-by":"publisher","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":"Nature Communications"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"H2183","DOI":"10.1152\/ajpheart.1996.271.5.H2183","article-title":"Cardiomyocyte DNA synthesis and binucleation during murine development","volume":"271","author":"Soonpaa","year":"1996","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.bbamcr.2012.10.029","article-title":"Challenges measuring cardiomyocyte renewal","volume":"1833","author":"Soonpaa","year":"2013","journal-title":"Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1038\/emboj.2008.141","article-title":"Epidermal insulin\/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through rac activation","volume":"27","author":"Stachelscheid","year":"2008","journal-title":"The EMBO Journal"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.tcm.2010.02.011","article-title":"Epicardium and myocardium originate from a common cardiogenic precursor pool","volume":"20","author":"van Wijk","year":"2010","journal-title":"Trends in Cardiovascular Medicine"},{"key":"bib46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006922","article-title":"Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function","volume":"13","author":"Vincentz","year":"2017","journal-title":"PLOS Genetics"},{"key":"bib47","doi-asserted-by":"publisher","DOI":"10.1186\/s12861-019-0186-8","article-title":"Differential roles of insulin like growth factor 1 receptor and insulin receptor during embryonic heart development","volume":"19","author":"Wang","year":"2019","journal-title":"BMC Developmental Biology"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"H24","DOI":"10.1152\/ajpheart.00521.2018","article-title":"IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration","volume":"316","author":"Wodsedalek","year":"2019","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"H1045","DOI":"10.1152\/ajpheart.00697.2015","article-title":"Towards regenerating the mammalian heart: challenges in evaluating experimentally induced adult mammalian cardiomyocyte proliferation","volume":"310","author":"Zebrowski","year":"2016","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"10704","DOI":"10.1074\/jbc.M107068200","article-title":"Regulation of the murine Nfatc1 gene by NFATc2","volume":"277","author":"Zhou","year":"2002","journal-title":"The Journal of Biological Chemistry"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/53071\/elife-53071-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/53071\/elife-53071-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/53071","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:00:05Z","timestamp":1697058005000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/53071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,13]]},"references-count":50,"alternative-id":["10.7554\/eLife.53071"],"URL":"https:\/\/doi.org\/10.7554\/elife.53071","archive":["CLOCKSS"],"relation":{"has-review":[{"id-type":"doi","id":"10.7554\/eLife.53071.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.53071.sa1","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,13]]},"article-number":"e53071"}}