{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T16:08:36Z","timestamp":1787328516924,"version":"build-2736575974"},"reference-count":64,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Engineering and Physical Sciences Research Council (EPSRC) & Medical Research Council (MRC) Centre for Doctoral Training","award":["EP\/L014904\/1"],"award-info":[{"award-number":["EP\/L014904\/1"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>In contrast to mammals, lower vertebrates are capable of extraordinary myocardial regeneration thanks to the ability of their cardiomyocytes to undergo transient dedifferentiation and proliferation. Somatic cells can be temporarily reprogrammed to a proliferative, dedifferentiated state through forced expression of <jats:italic>Oct3\/4<\/jats:italic>, <jats:italic>Sox2<\/jats:italic>, <jats:italic>Klf4<\/jats:italic> and <jats:italic>c-Myc<\/jats:italic> (OSKM). Here, we aimed to induce transient reprogramming of mammalian cardiomyocytes <jats:italic>in vitro<\/jats:italic> utilising an OSKM-encoding non-integrating vector. Reprogramming factor expression in postnatal rat and mouse cardiomyocytes triggered rapid but limited cell dedifferentiation. Concomitantly, a significant increase in cell viability, cell cycle related gene expression and Ki67 positive cells was observed consistent with an enhanced cell cycle activation. The transient nature of this partial reprogramming was confirmed as cardiomyocyte-specific cell morphology, gene expression and contractile activity were spontaneously recovered by day 15 after viral transduction. This study provides the first evidence that adenoviral OSKM delivery can induce partial reprogramming of postnatal cardiomyocytes. Therefore, adenoviral mediated transient reprogramming could be a novel and feasible strategy to recapitulate the regenerative mechanisms of lower vertebrates.<\/jats:p>","DOI":"10.1371\/journal.pone.0251054","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T19:12:22Z","timestamp":1620241942000},"page":"e0251054","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transient reprogramming of postnatal cardiomyocytes to a dedifferentiated state"],"prefix":"10.1371","volume":"16","author":[{"given":"Thomas","family":"Kisby","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-0173","authenticated-orcid":true,"given":"Irene","family":"de L\u00e1zaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Stylianou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Cossu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-6672","authenticated-orcid":true,"given":"Kostas","family":"Kostarelos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"issue":"5","key":"pone.0251054.ref001","first-page":"H2183","article-title":"Cardiomyocyte DNA synthesis and binucleation during murine development","volume":"271","author":"MH Soonpaa","year":"1996","journal-title":"Am J Physiol"},{"issue":"3","key":"pone.0251054.ref002","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1093\/cvr\/cvq005","article-title":"Cardiomyocyte cell cycle control and growth estimation in vivo\u2014an analysis based on cardiomyocyte nuclei","volume":"86","author":"S Walsh","year":"2010","journal-title":"Cardiovasc Res"},{"issue":"5923","key":"pone.0251054.ref003","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1164680","article-title":"Evidence for cardiomyocyte renewal in humans","volume":"324","author":"O Bergmann","year":"2009","journal-title":"Science"},{"issue":"7432","key":"pone.0251054.ref004","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature11682","article-title":"Mammalian heart renewal by pre-existing cardiomyocytes","volume":"493","author":"SE Senyo","year":"2013","journal-title":"Nature"},{"issue":"7","key":"pone.0251054.ref005","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":"O Bergmann","year":"2015","journal-title":"Cell"},{"issue":"5601","key":"pone.0251054.ref006","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1126\/science.1077857","article-title":"Heart regeneration in zebrafish","volume":"298","author":"KD Poss","year":"2002","journal-title":"Science"},{"issue":"suppl 1","key":"pone.0251054.ref007","doi-asserted-by":"crossref","first-page":"11889","DOI":"10.1073\/pnas.1834204100","article-title":"Activation of Notch signaling pathway precedes heart regeneration in zebrafish","volume":"100","author":"\u00c1 Raya","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"pone.0251054.ref008","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1242\/dev.060897","article-title":"Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish","volume":"138","author":"JM Gonz\u00e1lez-Rosa","year":"2011","journal-title":"Development"},{"issue":"7288","key":"pone.0251054.ref009","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/nature08804","article-title":"Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes","volume":"464","author":"K Kikuchi","year":"2010","journal-title":"Nature"},{"issue":"7288","key":"pone.0251054.ref010","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":"C Jopling","year":"2010","journal-title":"Nature"},{"issue":"5","key":"pone.0251054.ref011","doi-asserted-by":"crossref","first-page":"369","DOI":"10.2459\/JCM.0b013e3283375900","article-title":"Transcriptomics approach to investigate zebrafish heart regeneration","volume":"11","author":"E Sleep","year":"2010","journal-title":"J Cardiovasc Med (Hagerstown)"},{"issue":"1","key":"pone.0251054.ref012","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ydbio.2014.12.002","article-title":"de Preux Charles A-S, Duruz V, Pfefferli C, Ja\u017awi\u0144ska A. 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Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo","volume":"100","author":"R Agah","year":"1997","journal-title":"J Clin Invest"},{"issue":"2","key":"pone.0251054.ref036","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0022-1759(94)90396-4","article-title":"A new rapid and simple non-radioactive assay to monitor and determine the proliferation of lymphocytes: an alternative to [3H] thymidine incorporation assay","volume":"170","author":"SA Ahmed","year":"1994","journal-title":"J Immunol Methods"},{"issue":"15","key":"pone.0251054.ref037","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1242\/jcs.01159","article-title":"Sequential myofibrillar breakdown accompanies mitotic division of mammalian cardiomyocytes","volume":"117","author":"P Ahuja","year":"2004","journal-title":"J Cell 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Schwartz","year":"1999","journal-title":"Development"},{"issue":"6","key":"pone.0251054.ref041","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.stem.2012.11.008","article-title":"A late transition in somatic cell reprogramming requires regulators distinct from the pluripotency network","volume":"11","author":"A Golipour","year":"2012","journal-title":"Cell Stem Cell"},{"issue":"4","key":"pone.0251054.ref042","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.stem.2012.08.002","article-title":"Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells","volume":"11","author":"N Festuccia","year":"2012","journal-title":"Cell Stem Cell"},{"issue":"6200","key":"pone.0251054.ref043","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/336684a0","article-title":"Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells","volume":"336","author":"RL Williams","year":"1988","journal-title":"Nature"},{"issue":"7200","key":"pone.0251054.ref044","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nature07056","article-title":"Dissecting direct reprogramming through integrative genomic analysis","volume":"454","author":"TS Mikkelsen","year":"2008","journal-title":"Nature"},{"issue":"5903","key":"pone.0251054.ref045","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1126\/science.1164270","article-title":"Generation of mouse induced pluripotent stem cells without viral vectors","volume":"322","author":"K Okita","year":"2008","journal-title":"Science"},{"issue":"11","key":"pone.0251054.ref046","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1002\/stem.201","article-title":"Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells","volume":"27","author":"W Zhou","year":"2009","journal-title":"Stem 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type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells","volume":"28","author":"JM Polo","year":"2010","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pone.0251054.ref051","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.stem.2011.06.007","article-title":"Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells","volume":"9","author":"O Bar-Nur","year":"2011","journal-title":"Cell Stem Cell"},{"issue":"7516","key":"pone.0251054.ref052","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nature13458","article-title":"Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells","volume":"513","author":"Z Shipony","year":"2014","journal-title":"Nature"},{"issue":"1","key":"pone.0251054.ref053","doi-asserted-by":"crossref","first-page":"e54754","DOI":"10.1371\/journal.pone.0054754","article-title":"In vivo cell reprogramming towards pluripotency by virus-free overexpression of defined factors","volume":"8","author":"A Yilmazer","year":"2013","journal-title":"PloS One"},{"key":"pone.0251054.ref054","first-page":"e50837","article-title":"In vivo reprogramming of adult somatic cells to pluripotency by overexpression of Yamanaka factors","volume":"82","author":"A Yilmazer","year":"2013","journal-title":"J Vis Exp"},{"issue":"29","key":"pone.0251054.ref055","doi-asserted-by":"crossref","first-page":"8312","DOI":"10.1016\/j.biomaterials.2014.05.086","article-title":"Generation of induced pluripotent stem cells from virus-free in vivo reprogramming of BALB\/c mouse liver cells","volume":"35","author":"I de L\u00e1zaro","year":"2014","journal-title":"Biomaterials"},{"issue":"1","key":"pone.0251054.ref056","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.ymthe.2018.10.014","article-title":"Non-viral, Tumor-free Induction of Transient Cell Reprogramming in Mouse Skeletal Muscle to Enhance Tissue Regeneration","volume":"27","author":"I de L\u00e1zaro","year":"2019","journal-title":"Mol Ther"},{"issue":"2","key":"pone.0251054.ref057","doi-asserted-by":"crossref","first-page":"2000141","DOI":"10.1002\/adtp.202000141","article-title":"Adenoviral Mediated Delivery of OSKM Factors Induces Partial Reprogramming of Mouse Cardiac Cells In Vivo","volume":"4","author":"T Kisby","year":"2021","journal-title":"Advanced Therapeutics"},{"issue":"9","key":"pone.0251054.ref058","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1038\/mt.2016.124","article-title":"In situ pluripotency factor expression promotes functional recovery from cerebral ischemia","volume":"24","author":"JH 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