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

Anne Schellenberg¹, Qiong Lin², Herdit Schüler³, Carmen M. Koch¹, Sylvia Joussen¹, Bernd Denecke⁴, Gudrun Walenda¹, Norbert Pallua⁵, Christoph V. Suschek⁵, Martin Zenke^1,², Wolfgang Wagner¹

¹Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, 52074 Aachen, Germany
²Institute for Biomedical Engineering - Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany
³Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
⁴Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University, 52074 Aachen, Germany
⁵Department of Plastic and Reconstructive Surgery, Hand Surgery, Burn Center, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany

Received: September 15, 2011Accepted: September 24, 2011Published: September 25, 2011

https://doi.org/10.18632/aging.100391

Copyright: © 2011 Schellenberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.