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LIF-mediated control of embryonic stem cell self-renewal emerges due to an autoregulatory loop

Ryan E. Davey^*, Kento Onishi^*, Alborz Mahdavi^*, and Peter W. Zandstra^*,,1

^* Institute of Biomaterials and Biomedical Engineering,

Department of Chemical, Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada

¹Correspondence: Terrence Donnelly Centre for Cellular and Biomolecular Research, 160 College St., 11th Floor, University of Toronto, Toronto ON, Canada, M5S 3E1. E-mail: peter.zandstra{at}utoronto.ca

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.—Davey, R. E., Onishi, K., Mahdavi, A., Zandstra, P. W. LIF-mediated control of embryonic stem cell self-renewal emerges due to an autoregulatory loop.

Key Words: positive feedback • cell signaling • Jak-STAT • threshold • systems biology