期刊
AGING-US
卷 3, 期 9, 页码 873-888出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100391
关键词
Mesenchymal stem cells; replicative senescence; long-term culture; colony forming units (CFU-f); karyotype; DNA-methylation; epigenetic
资金
- excellence initiative of the German federal government
- excellence initiative of the German state government
- Else Kroner-Fresenius Stiftung
- Stem Cell Network North Rhine Westphalia
Cells in culture undergo replicative senescence. In this study, we analyzed functional, genetic and epigenetic sequels of long-term culture in human mesenchymal stem cells (MSC). Already within early passages the fibroblastoid colony-forming unit (CFU-f) frequency and the differentiation potential of MSC declined significantly. Relevant chromosomal aberrations were not detected by karyotyping and SNP-microarrays. Subsequently, we have compared DNA-methylation profiles with the Infinium HumanMethylation27 Bead Array and the profiles differed markedly in MSC derived from adipose tissue and bone marrow. Notably, all MSC revealed highly consistent senescence-associated modifications at specific CpG sites. These DNA-methylation changes correlated with histone marks of previously published data sets, such as trimethylation of H3K9, H3K27 and EZH2 targets. Taken together, culture expansion of MSC has profound functional implications - these are hardly reflected by genomic instability but they are associated with highly reproducible DNA-methylation changes which correlate with repressive histone marks. Therefore replicative senescence seems to be epigenetically controlled.
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