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Background  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 (P S ) and prolonged (P L ) passages, both in standard and low [O 2 ] (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 P L  or P S  surprisingly showed a quite significant fraction (69%) of upregulated miRNAs in P L  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/Gtl 2), cultured at 21 and 3% [O 2 ], was also significantly higher in P L  than in P S  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.

Deregulation of the imprinted DLK1-DIO3 locus ncRNAs is associated with replicative senescence of human adipose-derived stem cells