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dc.contributor.authorGarcia-Lopez, Silvia 
dc.contributor.authorAlbo-Castellanos, Carmen 
dc.contributor.authorUrdinguio, Rocio G
dc.contributor.authorCanon, Susana 
dc.contributor.authorSanchez-Cabo, Fatima 
dc.contributor.authorMartínez-Serrano, Alberto
dc.contributor.authorFraga, Mario F
dc.contributor.authorBernad, Antonio 
dc.date.accessioned2019-02-07T11:45:55Z
dc.date.available2019-02-07T11:45:55Z
dc.date.issued2018
dc.identifier.citationPLoS One. 2018; 13(11):e0206534es_ES
dc.identifier.issn1932-6203es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7139
dc.description.abstractBACKGROUND: Human adult adipose-derived stem cells (hADSCs) have become the most promising cell source for regenerative medicine. However the prolonged ex vivo expansion periods required to obtain the necessary therapeutic dose promotes progressive senescence, with the concomitant reduction of their therapeutic potential. AIM AND SCOPE: A better understanding of the determinants of hADSC senescence is needed to improve biosafety while preserving therapeutic efficiency. Here, we investigated the association between deregulation of the imprinted DLK1-DIO3 region and replicative senescence in hADSC cultures. METHODS: We compared hADSC cultures at short (PS) and prolonged (PL) passages, both in standard and low [O2] (21 and 3%, respectively), in relation to replicative senescence. hADSCs were evaluated for expression alterations in the DLK1-DIO3 region on chromosome 14q32, and particularly in its main miRNA cluster. RESULTS: Comparison of hADSCs cultured at PL or PS surprisingly showed a quite significant fraction (69%) of upregulated miRNAs in PL cultures mapping to the imprinted 14q32 locus, the largest miRNA cluster described in the genome. In agreement, expression of the lncRNA MEG3 (Maternally Expressed 3; Meg3/Gtl2), cultured at 21 and 3% [O2], was also significantly higher in PL than in PS passages. During hADSC replicative senescence the AcK16H4 activating mark was found to be significantly associated with the deregulation of the entire DLK1-DIO3 locus, with a secondary regulatory role for the methylation of DMR regions. CONCLUSION: A direct relationship between DLK1-DIO3 deregulation and replicative senescence of hADSCs is reported, involving upregulation of a very significant fraction of its largest miRNA cluster (14q32.31), paralleled by the progressive overexpression of the lncRNA MEG3, which plays a central role in the regulation of Dlk1/Dio3 activation status in mice.es_ES
dc.description.sponsorshipThis work was supported by grants to AB from the Spanish Ministry of Economy, Industry (SAF2015-70882-R; AEI/FEDER, UE), Comunidad Autonoma de Madrid (S2010/BMD-2420), Instituto Salud Carlos III (RETICS TerCel, RD12/0019/0018) and the European Commission (FP7-HEALTH2009/CARE-MI). AMS was supported by grants from the MINECO (SAF2010–17167) and Instituto Salud Carlos III (RETICS TerCel, RD12/0019/0013), and MFF and RGU by grants from the Plan Nacional de I+D+I 2013-2016/FEDER (PI15/ 00892), the Asturias Regional Government (GRUPIN14-052), the IUOPA (Obra Social Cajastur) and the Fundacio´n Cientıfica de la AECC. SGL held a predoctoral fellowship from the Spanish Programa de Formacion del Profesorado Universitario.es_ES
dc.language.isoenges_ES
dc.publisherPublic Library of Sciencees_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleDeregulation of the imprinted DLK1-DIO3 locus ncRNAs is associated with replicative senescence of human adipose-derived stem cellses_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID30395586es_ES
dc.format.volume13es_ES
dc.format.number11es_ES
dc.format.pagee0206534es_ES
dc.identifier.doi10.1371/journal.pone.0206534es_ES
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España)es_ES
dc.contributor.funderComunidad de Madrides_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderEuropean Commissiones_ES
dc.contributor.funderGobierno del Principado de Asturiases_ES
dc.contributor.funderAsociación Española Contra el Canceres_ES
dc.contributor.funderFundación Cajastures_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1932-6203es_ES
dc.relation.publisherversionhttps://doi.org/10.1371/journal.pone.0206534es_ES
dc.identifier.journalPloS onees_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Antiguos CNICes_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformáticaes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/242038/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2015-70882-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0019/0018es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0019/0013es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2010-17167es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI15/00892es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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