title: LIF-mediated control of embryonic stem cell self-renewal emerges due to an autoregulatory loop.
abstract: Stem cells convert graded stimuli into all-or-nothing cell-fate responses. We investigated how embryonic stem cells (ESCs) convert leukemia inhibitory factor (LIF) concentration into an all-or-nothing cell-fate decision (self-renewal). Using a combined experimental/computational approach we demonstrate unexpected switch-like (on/off) signaling in response to LIF. This behavior emerges over time due to a positive feedback loop controlling transcriptional expression of LIF signaling pathway components. The autoregulatory loop maintains robust pathway responsiveness ("on") at sufficient concentrations of exogenous LIF, while autocrine signaling and low concentrations of exogenous LIF cause ESCs to adopt the weakly responsive ("off") state of differentiated cells. We demonstrate that loss of ligand responsiveness is reversible and precedes loss of the ESC transcription factors Oct4 and Nanog, suggesting an early step in the hierarchical control of differentiation. While endogenously produced ligands were insufficient to sustain the "on" state, they buffer it, influencing the timing of differentiation. These results demonstrate a novel switch-like behavior, which establishes the LIF threshold for ESC self-renewal.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Davey
authors.forename: Kento
authors.initials: K
authors.lastname: Onishi
authors.forename: Alborz
authors.initials: A
authors.lastname: Mahdavi
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000172:deficiency / Q000502:physiology; D053606:Receptors, OSM-LIF / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C494200:Il6st protein, mouse; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130