Research Paper Volume 3, Issue 9 pp 873—888
Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks
- 1 Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, 52074 Aachen, Germany
- 2 Institute for Biomedical Engineering - Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany
- 3 Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- 4 Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University, 52074 Aachen, Germany
- 5 Department of Plastic and Reconstructive Surgery, Hand Surgery, Burn Center, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
Received: September 15, 2011 Accepted: September 24, 2011 Published: September 25, 2011
https://doi.org/10.18632/aging.100391How to Cite
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 colonyforming 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.