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

Autor: Fátima Sánchez-Cabo, Susana Cañón, Silvia García-López, Alberto Martínez-Serrano, Carmen Albo-Castellanos, Mario F. Fraga, Rocío G. Urdinguio, Antonio Bernad
Přispěvatelé: UAM. Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CBM), European Commission, Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, Comunidad de Madrid, Gobierno del Principado de Asturias (España), Asociación Española Contra el Cáncer, Fundación Cajastur
Jazyk: Spanish; Castilian
Rok vydání: 2018
Předmět:
0301 basic medicine
Aging
Physiology
lcsh:Medicine
Determinants of hADSC
Biochemistry
Pediatrics
Epigenesis
Genetic
Mice
miRNA cluster (14q32.31)
Medicine and Health Sciences
European commission
lcsh:Science
Cells
Cultured
Cellular Senescence
Multidisciplinary
DNA methylation
Biología y Biomedicina / Biología
Chromatin
3. Good health
Up-Regulation
Nucleic acids
Intercellular Signaling Peptides and Proteins
Christian ministry
Epigenetics
RNA
Long Noncoding
Biological Cultures
DNA modification
Chromatin modification
Research Article
Chromosome biology
Cell biology
Cells
Research and Analysis Methods
Senescence
Iodide Peroxidase
Deregulation
03 medical and health sciences
Genomic Imprinting
Political science
Genetics
Animals
Humans
Non-coding RNA
Cell Proliferation
Chromosomes
Human
Pair 14
Natural antisense transcripts
Biology and life sciences
lcsh:R
Calcium-Binding Proteins
Membrane Proteins
Mesenchymal Stem Cells
DNA
Cell Cultures
Gene regulation
MicroRNAs
030104 developmental biology
Gene Expression Regulation
Genetic Loci
Long non-coding RNAs
RNA
lcsh:Q
Gene expression
Physiological Processes
Humanities
Organism Development
Developmental Biology
Zdroj: Scopus
RUO. Repositorio Institucional de la Universidad de Oviedo
instname
Digital.CSIC. Repositorio Institucional del CSIC
PLoS ONE
Biblos-e Archivo. Repositorio Institucional de la UAM
Repisalud
Instituto de Salud Carlos III (ISCIII)
Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid
Consejería de Sanidad de la Comunidad de Madrid
PLoS ONE, Vol 13, Iss 11, p e0206534 (2018)
ISSN: 2015-7088
Popis: 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) and prolonged (P) passages, both in standard and low [O] (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 or P surprisingly showed a quite significant fraction (69%) of upregulated miRNAs in P 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% [O], was also significantly higher in P than in P 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.
Ministry of Economy, Industry (SAF2015-70882-R; AEI/FEDER, UE), Comunidad Autónoma de Madrid (S2010/BMD-2420), Instituto Salud Carlos III (RETICS TerCel, RD12/0019/0018) and the European Commission (FP7-HEALTH-2009/CARE-MI)
Databáze: OpenAIRE
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