Oct4 and Nanog Directly Regulate Dnmt1 to Maintain Self-Renewal and Undifferentiated State in Mesenchymal Stem Cells

The roles of Oct4 and Nanog in maintaining self-renewal and undifferentiated status of adult stem cells are unclear. Here, increase in Oct4 and Nanog expression along with increased proliferation and differentiation potential but decreased spontaneous differentiation were observed in early-passage (...

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Published in:Molecular cell 2012-07, Vol.47 (2), p.169-182
Main Authors: Tsai, Chih-Chien, Su, Pei-Fen, Huang, Yi-Feng, Yew, Tu-Lai, Hung, Shih-Chieh
Format: Article
Language:English
Subjects:
adult stem cells
Animals
Cell Differentiation
Cell Lineage
Cell Proliferation
cells
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases - physiology
Gene Expression Regulation
genes
Humans
Hypoxia
Mesenchymal Stromal Cells - cytology
Mice
Models, Biological
Octamer Transcription Factor-3 - physiology
protein-protein interactions
proteins
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Summary:The roles of Oct4 and Nanog in maintaining self-renewal and undifferentiated status of adult stem cells are unclear. Here, increase in Oct4 and Nanog expression along with increased proliferation and differentiation potential but decreased spontaneous differentiation were observed in early-passage (E), hypoxic culture (H), and p21 knockdown (p21KD) mesenchymal stem cells (MSCs) compared to late-passage (L), normoxic culture (N), and scrambled shRNA-overexpressed (Scr) MSCs. Knockdown of Oct4 and Nanog in E, H, and p21KD MSCs decreased proliferation and differentiation potential and enhanced spontaneous differentiation, whereas overexpression of Oct4 and Nanog in L, N, and Scr MSCs increased proliferation and differentiation potential and suppressed spontaneous differentiation. Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation. These data demonstrate the important roles of Oct4 and Nanog in maintaining MSC properties. [Display omitted] ► Increases in stem cell properties correlate with Oct4 and Nanog expression in MSCs ► Knockdown of Oct4 and Nanog decreases stem cell properties in early-passage MSCs ► Overexpression of Oct4 and Nanog increases stem cell properties in late-passage MSCs ► Oct4 and Nanog upregulate Dnmt1 to maintain self-renewal and undifferentiated state
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2012.06.020