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Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: Role of the BMP-4 gene

 Robert R. Bowers  ;  Jae Woo Kim  ;  Tamara C. Otto  ;  M. Daniel Lane 
 Proceedings of the National Academy of Sciences of the United States of America, Vol.103(35) : 13022-13027, 2006 
Journal Title
 Proceedings of the National Academy of Sciences of the United States of America 
Issue Date
Adipocytes/cytology* ; Adipocytes/drug effects ; Animals ; Azacitidine/pharmacology ; Bone Morphogenetic Protein 4 ; Bone Morphogenetic Proteins/antagonists & inhibitors ; Bone Morphogenetic Proteins/genetics* ; Bone Morphogenetic Proteins/metabolism ; Carrier Proteins/metabolism ; Cell Count ; Cell Lineage*/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; DNA Methylation*/drug effects ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Humans ; Mesoderm/cytology ; Mice ; Phenotype ; Promoter Regions, Genetic/drug effects ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction/drug effects ; Stem Cells/cytology* ; Stem Cells/drug effects
5-azacytidine ; adipogenesis ; determination ; mesenchymal stem cell ; preadipocyte
Previous studies showed that exposure of C3H10T1/2 stem cells to bone morphogenetic protein-4 (BMP-4) produced cells that convert into adipocytes at high frequency when treated with differentiation inducers. In the present investigation, an independent approach shows that BMP-4 is required for stable commitment of pluripotent stem cells to the adipocyte lineage. Exposure of proliferating 10T1/2 stem cells to 5-azacytidine, a potent DNA methylation inhibitor, gave rise to a subpopulation of cells that can be cloned and that have the capacity to undergo conversion into adipocytes upon treatment with terminal differentiation inducers. Detailed studies performed with a cloned committed subline, the A33 line, verified stable adipocyte lineage determination in the absence of exogenous BMP-4. Remarkably, this cell line expresses and secretes BMP-4 during proliferation in the same time window that exogenous BMP-4 must be added to naïve 10T1/2 cells to induce maximal adipocyte commitment. Furthermore, exposure of A33 cells to noggin, a naturally occurring BMP-4–binding antagonist, during this critical time window blocks subsequent differentiation. The role of BMP-4 in adipocyte lineage commitment is further strengthened by gene expression profiling of proliferating 10T1/2 stem cells and A33 preadipocytes. These findings revealed changes in the molecular circuitry, specifically coordinated changes in the expression of members of the BMP-4 signaling pathway, that distinguish A33 preadipocytes from uncommitted parental 10T1/2 stem cells. Together, these studies provide compelling evidence for the participation of BMP-4 in adipocyte lineage determination.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Woo(김재우) ORCID logo https://orcid.org/0000-0001-5456-9495
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