title: Murine Embryonic Stem Cell Plasticity Is Regulated through Klf5 and Maintained by Metalloproteinase MMP1 and Hypoxia.
abstract: Mouse embryonic stem cells (mESCs) are expanded and maintained pluripotent in vitro in the presence of leukemia inhibitory factor (LIF), an IL6 cytokine family member which displays pleiotropic functions, depending on both cell maturity and cell type. LIF withdrawal leads to heterogeneous differentiation of mESCs with a proportion of the differentiated cells apoptosising. During LIF withdrawal, cells sequentially enter a reversible and irreversible phase of differentiation during which LIF addition induces different effects. However the regulators and effectors of LIF-mediated reprogramming are poorly understood. By employing a LIF-dependent 'plasticity' test, that we set up, we show that Klf5, but not JunB is a key LIF effector. Furthermore PI3K signaling, required for the maintenance of mESC pluripotency, has no effect on mESC plasticity while displaying a major role in committed cells by stimulating expression of the mesodermal marker Brachyury at the expense of endoderm and neuroectoderm lineage markers. We also show that the MMP1 metalloproteinase, which can replace LIF for maintenance of pluripotency, mimics LIF in the plasticity window, but less efficiently. Finally, we demonstrate that mESCs maintain plasticity and pluripotency potentials in vitro under hypoxic/physioxic growth conditions at 3% O2 despite lower levels of Pluri and Master gene expression in comparison to 20% O2.
authors.affiliation: Univ. Bordeaux, CIRID, UMR5164, F-33 000 Bordeaux, France.|CNRS, CIRID, UMR 5164, F-33 000 Bordeaux, France.|Lebanese University, Beyrouth, Liban.
authors.forename: Aya Abou
authors.initials: AA
authors.lastname: Hammoud
authors.affiliation: Univ. Bordeaux, CIRID, UMR5164, F-33 000 Bordeaux, France.|CNRS, CIRID, UMR 5164, F-33 000 Bordeaux, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Kirstein
authors.affiliation: Univ. Bordeaux, CIRID, UMR5164, F-33 000 Bordeaux, France.|CNRS, CIRID, UMR 5164, F-33 000 Bordeaux, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Mournetas
authors.affiliation: Univ. Bordeaux, CIRID, UMR5164, F-33 000 Bordeaux, France.|CNRS, CIRID, UMR 5164, F-33 000 Bordeaux, France.
authors.forename: Anais
authors.initials: A
authors.lastname: Darracq
authors.affiliation: Univ. Bordeaux, CIRID, UMR5164, F-33 000 Bordeaux, France.|CNRS, CIRID, UMR 5164, F-33 000 Bordeaux, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Broc
authors.affiliation: Univ. Bordeaux, CIRID, UMR5164, F-33 000 Bordeaux, France.|CNRS, CIRID, UMR 5164, F-33 000 Bordeaux, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Blanchard
authors.affiliation: Lebanese University, Beyrouth, Liban.
authors.forename: Dana
authors.initials: D
authors.lastname: Zeineddine
authors.affiliation: Lebanese University, Beyrouth, Liban.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mortada
authors.affiliation: Univ. Bordeaux, CIRID, UMR5164, F-33 000 Bordeaux, France.|CNRS, CIRID, UMR 5164, F-33 000 Bordeaux, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Boeuf
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D000066670:Cell Plasticity / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000494:pharmacology*; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C584097:JunB protein, mouse; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D053605:Leukemia Inhibitory Factor; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D020781:Matrix Metalloproteinase 1