title: Cytostatic Effect of Repeated Exposure to Simvastatin: A Mechanism for Chronic Myotoxicity Revealed by the Use of Mesodermal Progenitors Derived from Human Pluripotent Stem Cells.
abstract: Statin treatment of hypercholesterolemia can lead to chronic myotoxicity which is, in most cases, alleviated by drug withdrawal. Cellular and molecular mechanisms of this adverse effect have been elusive, in particular because of the lack of in vitro models suitable for long-term exposures. We have taken advantage of the properties of human pluripotent stem cell-derived mesodermal precursors, that can be maintained unaltered in vitro for a long period of time, to develop a model of repeated exposures to simvastatin during more than 2 weeks. This approach unveiled major differences, both in functional and molecular terms, in response to single versus repeated-dose exposures to simvastatin. The main functional effect of the in vitro simvastatin-induced long-term toxicity was a loss of proliferative capacity in the absence of concomitant cell death, revealing that cytostatic effect could be a major contributor to statin-induced myotoxicity. Comparative analysis of molecular modifications induced by simvastatin short-term versus prolonged exposures demonstrated powerful adaptive cell responses, as illustrated by the dramatic decrease in the number of differentially expressed genes, distinct biological pathway enrichments, and distinct patterns of nutrient transporters expressed at the cell surface. This study underlines the potential of derivatives of human pluripotent stem cells for developing new approaches in toxicology, in particular for chronic toxicity testing.
authors.affiliation: INSERM U861, I-Stem, Evry Cedex, Paris, France.|UEVE U861, I-Stem, Evry Cedex, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Peric
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Isabel
authors.initials: I
authors.lastname: Barragan
authors.affiliation: CECS/AFM, I-Stem, Evry Cedex, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Giraud-Triboult
authors.affiliation: INSERM U861, I-Stem, Evry Cedex, Paris, France.|UEVE U861, I-Stem, Evry Cedex, Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Egesipe
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.|INSERM U1111, Lyon, France.
authors.forename: Laurène
authors.initials: L
authors.lastname: Meyniel-Schicklin
authors.affiliation: METAFORA Biosystems, Evry, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Cousin
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.|INSERM U1111, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lotteau
authors.affiliation: METAFORA Biosystems, Evry, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Petit
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, Université de Montpellier, Montpellier, France.
authors.forename: Jawida
authors.initials: J
authors.lastname: Touhami
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, Université de Montpellier, Montpellier, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Battini
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, Université de Montpellier, Montpellier, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Sitbon
authors.affiliation: INSERM U861, I-Stem, Evry Cedex, Paris, France.|UEVE U861, I-Stem, Evry Cedex, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Pinset
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.affiliation: CECS/AFM, I-Stem, Evry Cedex, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Laustriat
authors.affiliation: INSERM U861, I-Stem, Evry Cedex, Paris, France.|UEVE U861, I-Stem, Evry Cedex, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects*; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D019821:Simvastatin
keywords: Chronic toxicity; Cytostatic agent; Mesoderm; Pluripotent stem cells; Simvastatin