Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks.
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.
Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, 52074 Aachen, Germany.
Anne
A
Schellenberg
Qiong
Q
Lin
Herdit
H
Schüler
Carmen M
CM
Koch
Sylvia
S
Joussen
Bernd
B
Denecke
Gudrun
G
Walenda
Norbert
N
Pallua
Christoph V
CV
Suschek
Martin
M
Zenke
Wolfga
W
Wagner
D000273:Adipose Tissue / Q000166:cytology; D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007621:Karyotyping; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D046228:Microarray Analysis / Q000295:instrumentation / Q000379:methods; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D006657:Histones