Ligand/receptor signaling threshold (LIST) model accounts for gp130-mediated embryonic stem cell self-renewal responses to LIF and HIL-6

Stem Cells
Sowmya ViswanathanPeter W Zandstra

Abstract

We previously demonstrated that embryonic stem (ES) cell self-renewal required sustained signaling by leukemia inhibitory factor (LIF) in a concentration-dependent manner, allowing us to hypothesize that thresholds in ligand-receptor signaling modulate stem cell differentiation control. To test this hypothesis, we have experimentally and computationally compared the abilities of two gp130-signaling cytokines (LIF and Hyper-interleukin-6 [HIL-6]) to sustain ES cell self-renewal. Quantitative measurements of ES cell phenotypic markers (stage-specific embryonic antigen-1 and E-cadherin), functional assays (alkaline phosphatase activity and embryoid body formation efficiency), and transcription factor (Oct-4) expression over a range of LIF and HIL-6 concentrations demonstrated a superior ability of LIF to maintain ES cell pluripotentiality at higher concentrations (> or =500 pM). Additionally, we observed distinct qualitative differences in the ES cell self-renewal dose response profiles between the two cytokines. A computational model permitted calculation of the number of signaling complexes as a function of receptor expression, ligand concentration, and ligand/receptor-binding properties, generating predictions for the degree of...Continue Reading

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Citations

Jun 3, 2006·Medical Microbiology and Immunology·Jürgen Scheller, Stefan Rose-John
Oct 20, 2005·Journal of Bioscience and Bioengineering·Kiyoshi YasukawaTakahiko Ishiguro
Nov 13, 2008·Cytotechnology·Sowmya Viswanathan, Peter W Zandstra
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