2026-06-14T03:31:55Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/71392024-10-31T11:45:52Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605col_20.500.12105_19607
Repisalud
author
Garcia-Lopez, Silvia
author
Albo-Castellanos, Carmen
author
Urdinguio, Rocio G
author
Canon, Susana
author
Sanchez-Cabo, Fatima
author
Martínez-Serrano, Alberto
author
Fraga, Mario F
author
Bernad, Antonio
funder
Ministerio de Economía, Industria y Competitividad (España)
funder
Comunidad de Madrid (España)
funder
Instituto de Salud Carlos III
funder
Unión Europea. Comisión Europea
funder
Gobierno del Principado de Asturias (España)
funder
Asociación Española Contra el Cáncer
funder
Fundación Cajastur
2019-02-07T11:45:55Z
2019-02-07T11:45:55Z
2018
PLoS One. 2018; 13(11):e0206534
10.1371/journal.pone.0206534
1932-6203
1932-6203
PloS one
30395586
http://hdl.handle.net/20.500.12105/7139
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 (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.
eng
Deregulation of the imprinted DLK1-DIO3 locus ncRNAs is associated with replicative senescence of human adipose-derived stem cells
journal article
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
URL
https://repisalud.isciii.es/bitstreams/f723995f-1832-424b-ac52-3e7078750d42/download
File
MD5
049b5e6b6cb4d1a19f0826396ac3e924
2122253
application/pdf
DeregulationOfTheImprintedDLK1-DIO3_2018.pdf
URL
https://repisalud.isciii.es/bitstreams/a3464189-c083-45ac-b561-5c27748f533f/download
File
MD5
d3d6785f1742e61b86f3ee96d5771b13
217344
image/tiff
pone.0206534.s002.tif
URL
https://repisalud.isciii.es/bitstreams/77cc9299-4f89-4d32-b1e7-c59079d44296/download
File
MD5
0b4cabb18e68b27d15ca4fc6b8e553e3
1966268
image/tiff
pone.0206534.s001.tif
URL
https://repisalud.isciii.es/bitstreams/bd8091aa-132c-48c6-a592-0d321c2c2c0e/download
File
MD5
03b07f7f260c510165f39f285ae052b6
255748
image/tiff
pone.0206534.s003.tif
URL
https://repisalud.isciii.es/bitstreams/c349e2f1-a188-472f-940d-f90f9996d23f/download
File
MD5
fde3ba85aa4d4449644864764125fd86
119538
application/vnd.openxmlformats-officedocument.wordprocessingml.document
pone.0206534.s007.docx
URL
https://repisalud.isciii.es/bitstreams/dfc84ed4-b12c-4bf5-9d67-cb92d36a08df/download
File
MD5
9d3a3be724110f2cf6e5c756f7025381
133097
application/pdf
pone.0206534.s006.pdf
URL
https://repisalud.isciii.es/bitstreams/ca9e313e-aa9b-475a-8f8a-7b7276efa8ca/download
File
MD5
e8efb7f91ad5ed5d0fc175c788dc84d1
37009
application/pdf
pone.0206534.s005.pdf
URL
https://repisalud.isciii.es/bitstreams/7723f9ec-79be-4117-9215-20717ca19739/download
File
MD5
b04505bf538c888759de0bf58aa5900d
658896
image/tiff
pone.0206534.s004.tif
URL
https://repisalud.isciii.es/bitstreams/572c88d7-427e-4294-a132-d94768b592fa/download
File
MD5
fd7ee98a255e2a52e61c3937b159498c
37698
application/vnd.openxmlformats-officedocument.wordprocessingml.document
pone.0206534.s009.docx
URL
https://repisalud.isciii.es/bitstreams/e7317a3e-8173-4d58-b506-d15b92a86ddb/download
File
MD5
8bb3131b6698fc719c8b381e013850eb
1616852
image/tiff
pone.0206534.s008.tif
URL
https://repisalud.isciii.es/bitstreams/64c3852a-bec2-4914-8450-ee28176877e7/download
File
MD5
84e7a35d0f0896e37a6799d414f62e16
57647
text/plain
DeregulationOfTheImprintedDLK1-DIO3_2018.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/0bfb1643-e59f-4810-ab2b-819ba133c814/download
File
MD5
00a9777c6da0f4ec69f19c13ee857a15
91177
text/plain
pone.0206534.s006.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/6c629160-b875-448b-b1e7-51d373070737/download
File
MD5
77c10fdfa22ed0de9251ffd9e2518792
6584
text/plain
pone.0206534.s005.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/7e5dfea6-663a-40ee-8a49-991395207297/download
File
MD5
36969784a13934714af671f7dc4ac265
6910
text/plain
pone.0206534.s007.docx.txt
URL
https://repisalud.isciii.es/bitstreams/e569fd03-ed56-4b49-8c06-259ee4ce57ac/download
File
MD5
931644202a398629bcc6c27418bdb5c6
7714
text/plain
pone.0206534.s009.docx.txt