1. Activation of protein kinase A and exchange protein directly activated by cAMP promotes adipocyte differentiation of human mesenchymal stem cells
- Author
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Bingbing Jia, Reidun K. Kopperud, Gérard Ailhaud, Nathalie Techer, Karsten Kristiansen, Ez-Zoubir Amri, Jinfu Wang, Rasmus Koefoed Petersen, Stein Ove Døskeland, Lise Madsen, Tao Ma, Dept. Biochemistry and Molecular Biology, Odense, University of Southern Denmark (SDU), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Biochemistry and Molecular Biology, Department of Biology [Copenhagen], Faculty of Science [Copenhagen], and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)
- Subjects
MESH: Signal Transduction ,IBMX ,Cellular differentiation ,lcsh:Medicine ,MESH: Thiazolidinediones ,Biochemistry ,Dexamethasone ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Adipocyte ,1-Methyl-3-isobutylxanthine ,Molecular Cell Biology ,Adipocytes ,Cyclic AMP ,MESH: Guanine Nucleotide Exchange Factors ,MESH: Obesity ,Guanine Nucleotide Exchange Factors ,Insulin ,MESH: Animals ,lcsh:Science ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,MESH: Cyclic AMP ,0303 health sciences ,Multidisciplinary ,Stem Cells ,MESH: 1-Methyl-3-isobutylxanthine ,Cell Differentiation ,MESH: Gene Expression Regulation ,Lipids ,Signaling Cascades ,Cell biology ,Adipose Tissue ,Adipogenesis ,MESH: Dexamethasone ,030220 oncology & carcinogenesis ,Signal transduction ,MESH: Adipose Tissue ,Research Article ,Signal Transduction ,MESH: Cell Differentiation ,medicine.medical_specialty ,MESH: Insulin ,MESH: Cyclic AMP-Dependent Protein Kinases ,MESH: Epoprostenol ,Biology ,Cell Line ,Rosiglitazone ,MESH: Gene Expression Profiling ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,Obesity ,Protein kinase A ,MESH: Mice ,MESH: Adipocytes ,030304 developmental biology ,MESH: Humans ,Gene Expression Profiling ,Mesenchymal stem cell ,lcsh:R ,Mesenchymal Stem Cells ,Cyclic AMP-Dependent Protein Kinases ,Epoprostenol ,MESH: Cell Line ,MESH: Mesenchymal Stem Cells ,Endocrinology ,chemistry ,Gene Expression Regulation ,Cell culture ,Thiazolidinediones ,lcsh:Q ,Developmental Biology - Abstract
Human mesenchymal stem cells are primary multipotent cells capable of differentiating into several cell types including adipocytes when cultured under defined in vitro conditions. In the present study we investigated the role of cAMP signaling and its downstream effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in adipocyte conversion of human mesenchymal stem cells derived from adipose tissue (hMADS). We show that cAMP signaling involving the simultaneous activation of both PKA- and Epac-dependent signaling is critical for this process even in the presence of the strong adipogenic inducers insulin, dexamethasone, and rosiglitazone, thereby clearly distinguishing the hMADS cells from murine preadipocytes cell lines, where rosiglitazone together with dexamethasone and insulin strongly promotes adipocyte differentiation. We further show that prostaglandin I(2) (PGI(2)) may fully substitute for the cAMP-elevating agent isobutylmethylxanthine (IBMX). Moreover, selective activation of Epac-dependent signaling promoted adipocyte differentiation when the Rho-associated kinase (ROCK) was inhibited. Unlike the case for murine preadipocytes cell lines, long-chain fatty acids, like arachidonic acid, did not promote adipocyte differentiation of hMADS cells in the absence of a PPARγ agonist. However, prolonged treatment with the synthetic PPARδ agonist L165041 promoted adipocyte differentiation of hMADS cells in the presence of IBMX. Taken together our results emphasize the need for cAMP signaling in concert with treatment with a PPARγ or PPARδ agonist to secure efficient adipocyte differentiation of human hMADS mesenchymal stem cells.
- Published
- 2012