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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 533962.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) regulates differentiation fate of human mesenchymal (stromal) stem cells through canonical Wnt signalling and C/EBP
Authors:Qiu, Weimin; Hu, Yuhui; Andersen, Tom E.; Jafari, Abbas; Li, Na; Wei Chen, Wei Chen; Kassem, Moustapha
Research Context:This work was supported in part by grants from the Danish Medical Research Council, the Danish Stem Cell Center, the Novo Nordisk Foundation, and a grant from the local government of the region of Southern Denmark.
Date of Publication (YYYY-MM-DD):2010-03-11
Title of Journal:The Journal of Biological Chemistry
Journal Abbrev.:J.Biol. Chem.
Issue / Number:19
Start Page:14438
End Page:14449
Copyright:© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Mechanisms controlling human multipotent mesenchymal (stromal) stem cell (hMSC) differentiation into osteoblasts or adipocytes are poorly understood. We have previously demonstrated that Wnt signaling in hMSC enhanced osteoblast differentiation and inhibited adipogenesis by comparing two hMSC cell lines overexpressing mutated forms of the Wnt co-receptor LRP5: T253I (hMSC-LRP5T253) and T244M (hMSC-LRP5T244) conducting high and low level of Wnt signaling, respectively. To explore the underlying molecular mechanisms, we compared gene expression profiles of hMSC-LRP5T253 and hMSC-LRP5T244 treated with Wnt3a using whole genome expression microarrays and found that TNFRSF19 is differentially up-regulated between the two cells lines. Bioinformatic analysis and dual luciferase assay of its promoter revealed that TNFRSF19 transcript 2 (TNFRSF19.2) is a target of canonical Wnt signaling. Knocking down TNFRSF19 in hMSC-LRP5T253 cells decreased Wnt3a-induced osteoblast differentiation marker alkaline phosphate activity and its overexpression in hMSC-LRP5T244 cells increased alkaline phosphate activity. In addition, TNFRSF19 was negatively regulated by adipogenic transcription factor CCAAT/enhancer-binding proteins (C/EBP). Knocking down TNFRSF19 in hMSC-LRP5T253 cells or its overexpression in hMSC-LRP5T244 cells significantly increased or decreased adipogenesis, respectively. In conclusion, we revealed a novel function of TNFRSF19 as a factor mediating differentiation signals that determine the hMSC differentiating fate into osteoblasts or adipocytes.
Free Keywords:C/EBP Transcription Factor;
Cell Differentiation;
Gene Regulation;
Stem Cell;
Wnt Pathway;
Human Mesenchymal Stem Cell;
Comment of the Author/Creator:To whom correspondence should be addressed: Laboratory for Molecular Endocrinology (KMEB), Dept. of Endocrinology and Metabolism, University Hospital of Odense, J. B. Winsløws Vej 25, 1, DK-5000 Odense C, Denmark. Tel.: 45-6550-4084; Fax: 45-6591-9653; E-mail:
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Laboratory for Molecular Endocrinology (KMEB), Department of Endocrinology and Metabolism, University Hospital of Odense, J. B. Winsløws Vej 25, 1, DK-5000 Odense C, Denmark;
2.Max Delbrück Centrum für Molekulare Medizin, Berlin Insitute for Medical Systems Biology, Robert-Rössle-Strasse 10, D-13125 Berlin-Buch, Germany;
3.Stem Cell Unit, Department of Anatomy, King Saud University, Riyadh 11451, Kingdom of Saudi Arabia.
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