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

Autor: Vincent Lotteau, Jean-Luc Battini, Anne-Laure Egesipe, Marc Peschanski, Magnus Ingelman-Sundberg, Jawida Touhami, Marc Sitbon, Laurène Meyniel-Schicklin, Christelle Cousin, Delphine Peric, Christian Pinset, Karine Giraud-Triboult, Isabel Barragan, Delphine Laustriat, Vincent Petit
Přispěvatelé: Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Karolinska Institutet [Stockholm], Department of Physiology and Pharmacology, Biologie cellulaire des infections virales – Cell biology of viral infection, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), METAFORA Biosystems, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AFM-Téléthon, INSERMCommission européenne FP7 et Cosmetics Europe / projet SCR&TOX, Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-Université d'Évry-Val-d'Essonne (UEVE), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), INSERM UEVE/UMR 861, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques ( I-STEM ), Université d'Évry-Val-d'Essonne ( UEVE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Évry-Val-d'Essonne ( UEVE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CECS/I-Stem, Association française contre les myopathies ( AFM-Téléthon ), Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Conan, Stéphanie
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Programmed cell death
cytostatic agent
[SDV]Life Sciences [q-bio]
Hypercholesterolemia
[ SDV.TOX ] Life Sciences [q-bio]/Toxicology
Cell
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
Pharmacology
Cell Line
03 medical and health sciences
0302 clinical medicine
mesoderm
medicine
Humans
simvastatin
Progenitor cell
Muscle
Skeletal
Induced pluripotent stem cell
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Chronic toxicity
Cell Proliferation
030304 developmental biology
0303 health sciences
Dose-Response Relationship
Drug
[ SDV ] Life Sciences [q-bio]
[ SDV.BC ] Life Sciences [q-bio]/Cellular Biology
Gene Expression Regulation
Developmental
Cell Differentiation
Cell Biology
In vitro
3. Good health
[SDV] Life Sciences [q-bio]
[SDV.TOX] Life Sciences [q-bio]/Toxicology
medicine.anatomical_structure
Simvastatin
[SDV.TOX]Life Sciences [q-bio]/Toxicology
Toxicity
Molecular Medicine
pluripotent stem cells
Transcriptome
030217 neurology & neurosurgery
chronic toxicity
Developmental Biology
medicine.drug
Zdroj: STEM CELLS
STEM CELLS, 2015, 33, pp.2936-2948. ⟨10.1002/stem.2107⟩
www.StemCells.com
STEM CELLS, AlphaMed Press, 2015, 33, pp.2936-2948. ⟨10.1002/stem.2107⟩
STEM CELLS, AlphaMed Press, 2015, 33, pp.2936-2948. 〈www.StemCells.com〉. 〈10.1002/stem.2107〉
ISSN: 1066-5099
DOI: 10.1002/stem.2107⟩
Popis: 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. Stem Cells 2015;33:2936–2948
Databáze: OpenAIRE
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