title: Cyclosporin A induces cardiac differentiation but inhibits hemato-endothelial differentiation of P19 cells.
abstract: Little is known about the mechanisms underlying the effects of Cyclosporin A (CsA) on the fate of stem cells, including cardiomyogenic differentiation. Therefore, we investigated the effects and the molecular mechanisms behind the actions of CsA on cell lineage determination of P19 cells. CsA induced cardiomyocyte-specific differentiation of P19 cells, with the highest efficiency at a concentration of 0.32 μM during embryoid body (EB) formation via activation of the Wnt signaling pathway molecules, Wnt3a, Wnt5a, and Wnt8a, and the cardiac mesoderm markers, Mixl1, Mesp1, and Mesp2. Interestingly, cotreatment of P19 cells with CsA plus dimethyl sulfoxide (DMSO) during EB formation significantly increases cardiac differentiation. In contrast, mRNA expression levels of hematopoietic and endothelial lineage markers, including Flk1 and Er71, were severely reduced in CsA-treated P19 cells. Furthermore, expression of Flk1 protein and the percentage of Flk1+ cells were severely reduced in 0.32 μM CsA-treated P19 cells compared to control cells. CsA significantly modulated mRNA expression levels of the cell cycle molecules, p53 and Cyclins D1, D2, and E2 in P19 cells during EB formation. Moreover, CsA significantly increased cell death and reduced cell number in P19 cells during EB formation. These results demonstrate that CsA induces cardiac differentiation but inhibits hemato-endothelial differentiation via activation of the Wnt signaling pathway, followed by modulation of cell lineage-determining genes in P19 cells during EB formation.
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Seung-Cheol
authors: SC
authors: Choi
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Hyunjoo
authors: H
authors: Lee
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Ji-Hyun
authors: JH
authors: Choi
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Jong-Ho
authors: JH
authors: Kim
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Chi-Yeon
authors: CY
authors: Park
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Hyung-Joon
authors: HJ
authors: Joo
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Jae-Hyoung
authors: JH
authors: Park
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Soon-Jun
authors: SJ
authors: Hong
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Cheol-Woong
authors: CW
authors: Yu
authors: Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.
authors: Do-Sun
authors: DS
authors: Lim
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D019070:Cell Lineage / Q000187:drug effects* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016572:Cyclosporine; D018398:Homeodomain Proteins; C101538:Mesp1 protein, mouse; C107407:Mesp2 protein, mouse; C464781:Mixl1 protein, mouse
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