Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks.
Aging (Albany NY), 2011/9;3(9):873-88.
Schellenberg A[1], Lin Q, Schüler H, Koch CM, Joussen S, Denecke B, Walenda G, Pallua N, Suschek CV, Zenke M, Wagner W
Affiliations
PMID: 22025769
Abstract
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.
MeSH terms
Adipose Tissue; Adult; Cell Differentiation; Cells, Cultured; Cellular Senescence; DNA Methylation; Epigenesis, Genetic; Female; Histones; Humans; Karyotyping; Male; Mesenchymal Stem Cells; Microarray Analysis; Middle Aged; Polymorphism, Single Nucleotide; Young Adult
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