| A bottleneck in the development of many stem cell therapies is to control cell fate decisions such as self-renewal. Activation of Jak/Stat3 signaling is sufficient for self-renewal of mouse embryonic stem cells in serum containing media. We demonstrate that the magnitude of transient activation of transcription factor Stat3, at different LIF concentrations, correlates with Oct4 expression at steady state. We therefore hypothesize that understanding the regulatory mechanism of Stat3 activation should yield insight into novel strategies to control of ESC self renewal. To capture Stat3 activation kinetics a biochemical model was developed and validated. To understand how the pathway is controlled a global sensitivity analysis of interactions in the pathway was performed. This analysis identified the group of parameters responsible for inhibition or enhanced activation of Stat3. The most important modules for signal control are nuclear phosphatase, nuclear export and feedback inhibition by SOCS3; these along with receptor trafficking control desensitization kinetics. |
