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      Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks

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          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.

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          Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.

          C Greider, E H Blackburn (1985)
          We have found a novel activity in Tetrahymena cell free extracts that adds tandem TTGGGG repeats onto synthetic telomere primers. The single-stranded DNA oligonucleotides (TTGGGG)4 and TGTGTGGGTGTGTGGGTGTGTGGG, consisting of the Tetrahymena and yeast telomeric sequences respectively, each functioned as primers for elongation, while (CCCCAA)4 and two nontelomeric sequence DNA oligomers did not. Efficient synthesis of the TTGGGG repeats depended only on addition of micromolar concentrations of oligomer primer, dGTP, and dTTP to the extract. The activity was sensitive to heat and proteinase K treatment. The repeat addition was independent of both endogenous Tetrahymena DNA and the endogenous alpha-type DNA polymerase; and a greater elongation activity was present during macronuclear development, when a large number of telomeres are formed and replicated, than during vegetative cell growth. We propose that the novel telomere terminal transferase is involved in the addition of telomeric repeats necessary for the replication of chromosome ends in eukaryotes.
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            The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.

            Adrian Bracken, Daniela Kleine-Kohlbrecher, Nikolaj Dietrich … (2007)
            The p16INK4A and p14ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing Polycomb-Repressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer.
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              Aging of mesenchymal stem cell in vitro

              Mandana Mohyeddin Bonab, Kamran Alimoghaddam, Fatemeh Talebian … (2006)
              Background A hot new topic in medical treatment is the use of mesenchymal stem cells (MSC) in therapy. The low frequency of this subpopulation of stem cells in bone marrow (BM) necessitates their in vitro expansion prior to clinical use. We evaluated the effect of long term culture on the senescence of these cells. Results The mean long term culture was 118 days and the mean passage number was 9. The average number of PD decreased from 7.7 to 1.2 in the 10th passage. The mean telomere length decreased from 9.19 Kbp to 8.7 kbp in the 9th passage. Differentiation potential dropped from the 6th passage on. The culture's morphological abnormalities were typical of the Hayflick model of cellular aging. Conclusion We believe that MSC enter senescence almost undetectably from the moment of in vitro culturing. Simultaneously these cells are losing their stem cell characteristics. Therefore, it is much better to consider them for cell and gene therapy early on.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (publisher-id): ImpactJ
                Title: Aging (Albany NY)
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1945-4589
                Publication date Collection: September 2011
                Publication date (Electronic): 25 September 2011
                Volume: 3
                Issue: 9
                Pages: 873-888
                Affiliations
                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
                Author notes
                Correspondence to: Wolfgang Wagner, MD/PhD; wwagner@ 123456ukaachen.de
                Article
                DOI: 10.18632/aging.100391
                PMC ID: 3227452
                PubMed ID: 22025769
                SO-VID: 15b27a3c-0c15-42c9-b146-9f4ac70ef26d
                Copyright © Copyright: © 2011 Schellenberg et al.
                License:

                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

                History
                Date received : 15 September 2011
                Date accepted : 24 September 2011
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Cell biology
                Keywords: dna-methylation,replicative senescence,karyotype,epigenetic,colony forming units (cfu-f),mesenchymal stem cells,long-term culture
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: dna-methylation, replicative senescence, karyotype, epigenetic, colony forming units (cfu-f), mesenchymal stem cells, long-term culture

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