title: Involvement of β-adrenoceptors in the differentiation of human induced pluripotent stem cells into mesodermal progenitor cells.
abstract: Previous studies suggest that β-adrenoceptor stimulation may enhance the cardiac differentiation of mouse embryonic stem (ES) cells. It remains unclear whether the differentiations of ES cells and induced pluripotent stem (iPS) cells rely on similar molecular mechanisms. In addition, no previous studies have shown that human iPS cells express β-adrenoceptors. Therefore, in the present study, we determined the involvement of β-adrenoceptors in the differentiation of human iPS cells into mesodermal progenitor cells. The induction of differentiation of human iPS cells into kinase insert domain receptor (KDR)-positive mesodermal progenitor cells was performed on feeder cells in a differentiation medium with basic fibroblast growth factor (bFGF), bone morphogenetic protein-4 (BMP-4), and activin A. When the iPS cells that were exposed to bFGF, BMP-4, and activin A were treated with L-isoproterenol (a β-adrenoceptor agonist) for 4 days, the expression of KDR was significantly increased compared to that in the cells that were not treated with L-isoproterenol. Pretreatment of the cells with either atenolol (a β1-adrenoceptor antagonist) or ICI-118551 (a β2-adrenoceptor antagonist) significantly inhibited the L-isoproterenol-induced increase in KDR expression. In addition, pretreatment with both H89 (a protein kinase A inhibitor) and SB203580 (a p38 MAPK inhibitor) significantly inhibited the L-isoproterenol-induced increase in KDR expression. Treatment with L-isoproterenol enhanced the phosphorylation of p38 MAPK in human iPS cells exposed to bFGF, BMP-4, and activin A. These results suggest that β-adrenoceptor stimulation in human iPS cells may enhance their differentiation into mesodermal progenitor cells via the activation of either protein kinase A or p38 MAPK.
authors.affiliation: Department of Pharmacology, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513, Japan. Electronic address: tishizu@ndmc.ac.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ishizuka
authors.affiliation: Department of Pharmacology, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Hazuki
authors.initials: H
authors.lastname: Goshima
authors.affiliation: Department of Pharmacology, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Ozawa
authors.affiliation: Department of Pharmacology, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D001262:Atenolol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D007093:Imidazoles; D007546:Isoquinolines; D011412:Propanolamines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; C026777:ICI 118551; D001262:Atenolol; D040301:Vascular Endothelial Growth Factor Receptor-2; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D007545:Isoproterenol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093642:SB 203580
keywords: Induced pluripotent stem cells; Protein kinase A; p38 MAPK; β-adrenoceptor