STAT3 Regulates Uterine Epithelial Remodeling and Epithelial-Stromal Crosstalk During Implantation

Abstract

Embryo implantation is regulated by a variety of endometrial factors, including cytokines, growth factors, and transcription factors. Earlier studies identified the leukemia inhibitory factor (LIF), a cytokine produced by uterine glands, as an essential regulator of implantation. LIF, acting via its cell surface receptor, activates the signal transducer and activator of transcription 3 (STAT3) in the uterine epithelial cells. However, the precise mechanism via which activated STAT3 promotes uterine function during implantation remains unknown. To identify the molecular pathways regulated by STAT3, we created SW(d/d) mice in which Stat3 gene is conditionally inactivated in uterine epithelium. The SW(d/d) mice are infertile due to a lack of embryo attachment to the uterine luminal epithelium and consequent implantation failure. Gene expression profiling of uterine epithelial cells of SW(d/d) mice revealed dysregulated expression of specific components of junctional complexes, including E-cadherin, α- and β-catenin, and several claudins, which critically regulate epithelial junctional integrity and embryo attachment. In addition, uteri of SW(d/d) mice exhibited markedly reduced stromal proliferation and differentiation, indicating that epithelial STAT3 controls stromal function via a paracrine mechanism. The stromal defect arose from a drastic reduction in the production of several members of the epidermal growth factor family in luminal epithelium of SW(d/d) uteri and the resulting lack of activation of epidermal growth factor receptor signaling and mitotic activity in the stromal cells. Collectively, our results uncovered an intricate molecular network operating downstream of STAT3 that regulates uterine epithelial junctional reorganization, and stromal proliferation, and differentiation, which are critical determinants of successful implantation.

Egr1 Protein Acts Downstream of Estrogen-Leukemia Inhibitory Factor (LIF)-STAT3 Pathway and Plays a Role during Implantation through Targeting Wnt4

“…The stromal localization of LIF is similar to phosphorylated STAT3 expression pattern (10). Conditional knock-out or transient suppression of STAT3 results in implantation failure, which suggests the critical role of STAT3 during implantation (11)(12)(13)(14). As a pleiotropic cytokine, LIF is also essential for mouse and human decidualization (15,16).…”

Embryo–epithelium interactions during implantation at a glance

“…Inactivation of uterine epithelial-specific Stat3 results in defects in epithelial polarity prior to implantation (Pawar et al, 2013). In addition, E-cadherin and several claudins that normally are downregulated at this stage are retained.…”

“…Moreover, paracrine signalling from the epithelium to the subjacent stroma through ligands of epidermal growth factor receptor (EGFR) in order to initiate decidualisation is also impaired. Although not all the uterine changes associated with implantation are absent, this subset of functional impairments is still sufficient to render the mice infertile, with embryos failing to attach to the epithelium (Pawar et al, 2013). Loss of uterine Alk3, a receptor for ligands of the type I BMP family, abolishes the suppression of epithelial proliferative activity that normally occurs at the time of implantation.…”

Molecular determinants of uterine receptivity

“…This signaling pathway, including Stat3 nuclear translocation in the luminal and glandular epithelium, is attenuated in LIF null mutant uteri (Cheng et al, 2001). Recent studies further demonstrate that uterine conditional deletion of Stat3 also induces implantation failure (Lee et al, 2013, Pawar et al, 2013, Sun et al, 2013. In the human, a low level of LIF is associated with unexplained recurrent abortion and infertility (Hambartsoumian, 1998, Piccinni et al, 1998.…”