title: Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood.
  
  
  RESULTS
  Human MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes.
  
  
  CONCLUSIONS
  Our results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation.
authors.affiliation: Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Li
authors.forename: Chenxiong
authors.initials: C
authors.lastname: Liu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xie
authors.forename: Pengyue
authors.initials: P
authors.lastname: Song
authors.forename: Robert C H
authors.initials: RC
authors.lastname: Zhao
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Yaojiong
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic; D004967:Estrogens / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D004967:Estrogens; D006657:Histones; D016222:Fibroblast Growth Factor 2