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Background  Potential therapeutic use of mesenchymal stem cells (MSCs) is likely to require large-scale in vitro expansion of the cells before transplantation. MSCs from adipose tissue can be cultured extensively until senescence. However, little is known on the differentiation potential of adipose stem cells (ASCs) upon extended culture and on associated epigenetic alterations. We examined the adipogenic differentiation potential of clones of human ASCs in early passage culture and upon senescence, and determined whether senescence was associated with changes in adipogenic promoter DNA methylation.    Results  ASC clones cultured to senescence display reduced adipogenic differentiation capacity in vitro, on the basis of limited lipogenesis and reduced transcriptional upregulation of  FABP4  and  LPL , two adipogenic genes, while  LEP  and  PPARG2  transcription remains unaffected. In undifferentiated senescent cells,  PPARG2  and  LPL  expression is unaltered, whereas  LEP  and  FABP4  transcript levels are increased but not in all clones. Bisulfite sequencing analysis of DNA methylation reveals overall relative stability of  LEP ,  PPARG2 ,  FABP4  and  LPL  promoter CpG methylation during senescence and upon differentiation. Mosaicism in methylation profiles is maintained between and within ASC clones, and any CpG-specific methylation change detected does not necessarily relate to differentiation potential. One exception to this contention is CpG No. 21 in the  LEP  promoter, whose senescence-related methylation may impair upregulation of the gene upon adipogenic stimulation.    Conclusion  Senescent ASCs display reduced in vitro differentiation ability and transcriptional activation of adipogenic genes upon differentiation induction. These restrictions, however, cannot in general be attributed to specific changes in DNA methylation at adipogenic promoters. There also seems to be a correlation between CpGs that are hypomethylated and important transcription factor binding sites.

Dynamics of adipogenic promoter DNA methylation during clonal culture of human adipose stem cells to senescence