Figure 6.

Proposed model showing that STAT3 is required for maintenance of the embryonic EPI and preservation of pluripotent stem cell identity. Stat3^mat−/− E4.5 blastocysts are collapsed with no OCT4- or NANOG-positive cells and reduced GATA6-positive cells in the ICM. Stat3^mat−/− E4.0 expanded blastocysts show a variable, abnormal phenotype with reduction or loss of NANOG- and GATA4-positive cells. There are consistent changes in expression of pluripotent and TE marker genes in the ICMs of Stat3^mat−/− blastocysts. IL-6, a cytokine produced by the blastocyst, acts in an autocrine fashion to ensure STAT3 phosphorylation. JAK1, a LIF- and IL-6-dependent downstream kinase, is responsible for STAT3 phosphorylation in the blastocyst. Stat3^mat−/− early blastocysts are morphologically normal, yet these embryos fail to form ICM-derived structures after in vitro outgrowth, and ESCs cannot be established. In vitro studies using ESCs and iPSCs indicate that STAT3 directly regulates the pluripotency gene network (Oct4, Nanog, and Klf4).