title: Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells.
abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT(1)R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression. Treatment with Ang II enhanced the phosphorylation of p38 MAPK in Col IV- exposed iPS cells. These results suggest that the stimulation of mouse iPS cells with AT(1)R may enhance LIF-induced DNA synthesis, by augmenting the generation of superoxide and activating JAK/STAT3, and that AT(1)R stimulation may enhance Col IV-induced differentiation into mesodermal progenitor cells via p38 MAPK activation.
authors.affiliation: Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan. tishizu@ndmc.ac.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Hazuki
authors.initials: H
authors.lastname: Goshima
authors.forename: Ayako
authors.initials: A
authors.lastname: Ozawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology; D053612:Janus Kinases / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013113:Spin Labels; D013234:Stem Cells / Q000166:cytology*; D013777:Tetrazoles / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003470:Culture Media; D003497:Cyclic N-Oxides; D053605:Leukemia Inhibitory Factor; D044140:Receptor, Angiotensin, Type 1; D050796:STAT3 Transcription Factor; D013113:Spin Labels; D013777:Tetrazoles; D000804:Angiotensin II; D004247:DNA; D053612:Janus Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C081643:candesartan; C001803:tempol