Exploring Confluence-Related Signalling to Modulate the Expression of Oct4 – A Role in Facilitating Mouse Somatic Cell Reprogramming?

Oct4 is uniformly expressed by all types of pluripotent cells and is essential for pluripotency. Oct4 is also the central reprogramming factor that is constant in most transcription factor cocktails used to generate iPS cells. This article discusses the mechanisms of regulating Oct4 expression by confluence-based Hgf and hypoxia signalling in mouse somatic cells. Stat3 is activated ligandindependently in confluent cells and triggers the formation of cell aggregates. Hgf signalling is preserved after confluence, stimulating β-catenin and Stat3 activity, which are both crucial for Oct4 transcription. Stat3 and β-catenin activities also help sustain cell survival and proliferation, resulting in the formation of cell spheres. Hypoxic conditions in spheres activate regulators of Oct4 and further induce Oct4 expression. Activation of the Oct4 gene depends on nuclear receptors Lrh1/SF1, Esrrb, and Rars. These interact synergistically to initiate Oct4 transcription through organizing a transcriptional initiation complex. cAMP signalling stimulates the production of the SF1/Lrh1 ligand. Esrrb agonist or estrogen might function in activating Esrrb, while Rars might be induced by hypoxia. Taken together, Oct4 expression is probably induced in mouse somatic cells by culturing post-confluence cells with media containing Hgf, Esrrb agonist, and cAMP agonist. Exploring confluence-related signalling to modulate the expression of Oct4 might be helpful in finding novel strategies for reprogramming somatic cells.