Role of uterine stromal-epithelial crosstalk in embryo implantation

Abstract

Embryo implantation is a crucial step for successful pregnancy. Prior to implantation, the luminal epithelium undergoes steroid hormone-induced structural and functional changes that render it competent for embryo attachment. Subsequent invasion of the embryo into the maternal tissue triggers differentiation of the underlying stromal cells to form the decidua, a transient tissue which supports the developing embryo. Many molecular cues of both stromal and epithelial origin have been identified that are critical mediators of this process. An important aspect of uterine biology is the elaborate crosstalk that occurs between these tissue compartments during early pregnancy through expression of paracrine factors regulated by the steroid hormones estrogen and progesterone. Aberrant expression of these factors often leads to implantation failure and infertility. Genetically-engineered mouse models have been instrumental in elucidating what these paracrine factors are, what drives their expression, and what their effects are on neighboring cells. This review provides an overview of several well-characterized signaling pathways that span both epithelial and stromal compartments and their function during implantation in the mouse.

Figure 1

Uterine luminal (pink) and glandular (purple) epithelial cells mediate changes in the stroma (green) through paracrine interactions. Dashed lines represent indirect activation or inhibition. Abbreviations: estrogen (E); estrogen receptor (ER); phosphorylated ER (pER); progesterone (P); progesterone receptor (PR); leukemia inhibitory factor (LIF); LIF receptor (LIFR); glycoprotein 130 (GP130); Janus kinase (JAK); signal transducer and activator of transcription 3 (STAT3); lactotransferrin (LTF); mucin 1 (MUC1); epidermal growth factor (EGF); EGF receptor (EGFR); Indian hedgehog (IHH); patched/smoothened (PTC/SMO); chicken ovalbumin upstream promoter transcription factor II (COUP-TFII); bone morphogenetic protein 2 (BMP2)

Figure 2

Uterine stroma (green) regulates epithelial (pink) function through paracrine factors. Dashed lines represent indirect activation or inhibition. Abbreviations: estrogen (E); estrogen receptor (ER); phosphorylated ER (pER); progesterone (P); progesterone receptor (PR); heart- and neural crest derivatives-expressed protein 2 (HAND2); fibroblast growth factors (FGFs); FGF receptor (FGFR); extracellular-signal-regulated kinases 1/2 (ERK1/2); mucin 1 (MUC1); lactotransferrin (LTF); insulin-like growth factor 1 (IGF1); IGF1 receptor (IGF1R); phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT); muscle segment homeobox genes 1/2 (MSX1/2); wingless-related MMTV integration site (WNT); proliferation (Prolif.)