Endometrial TGFβ signaling fosters early pregnancy development by remodeling the fetomaternal interface

Abstract

The endometrium is a unique and highly regenerative tissue with crucial roles during the reproductive lifespan of a woman. As the first site of contact between mother and embryo, the endometrium, and its critical processes of decidualization and immune cell recruitment, play a leading role in the establishment of pregnancy, embryonic development, and reproductive capacity. These integral processes are achieved by the concerted actions of steroid hormones and a myriad of growth factor signaling pathways. This review focuses on the roles of the transforming growth factor β (TGFβ) pathway in the endometrium during the earliest stages of pregnancy through the lens of immune cell regulation and function. We discuss how key ligands in the TGFβ family signal through downstream SMAD transcription factors and ultimately remodel the endometrium into a state suitable for embryo implantation and development. We also focus on the key roles of the TGFβ signaling pathway in recruiting uterine natural killer cells and their collective remodeling of the decidua and spiral arteries. By providing key details about immune cell populations and TGFβ signaling within the endometrium, it is our goal to shed light on the intricate remodeling that is required to achieve a successful pregnancy.

Keywords: decidualization; endometrium; pregnancy; pregnancy loss; transforming growth factor β; uterine natural killer cells.

Figure 1.. Schematic of the stages of early pregnancy and their regulation by TGFβ-family signaling pathways.

A viable early pregnancy is dependent on the successful transformation of the endometrium from its pre-implantation state to its receptive, decidualized state. TGFβ-family receptors and ligands are key regulators of various steps of this pathway and are instrumental at ensuring proper implantation, decidualization, and placentation. BMP7 and ALK3 drive endometrial receptivity and epithelial cell remodeling, which allow to embryo implantation to occur. Decidualization requires BMP2 and the BMP type 1 receptor, ALK2; however, ALK3 signaling in the stromal is also required for decidualization. The BMP type 2 receptor, BMPR2, and the TGFβ type 1 receptor, ALK5, are crucial for post-implantation development, uterine natural killer (uNK) cell infiltration, spiral artery development and placental development.

Figure 2.. Schematic of the TGFβ signaling pathway.

In the TGFβ signaling pathway, ligands such as TGFβ, BMPs, GDF or AMH signal by binding to a cell surface receptor complex comprised of two type 1 receptors and two type 2 receptors. The receptors have an intracellular kinase domain which upon ligand binding, leads to the activation of the downstream signaling pathways in the cell. The downstream signals are transmitted by the receptor-mediated phosphorylation of the SMAD transcription factors, which exist as trimers of SMAD1/SMAD5/SMAD4 or SMAD2/SMAD3/SMAD4, depending on the context of the ligand on the cell surface. Upon phosphorylation, the SMAD trimers are activated and translocate to the nucleus where they bind to conserved DNA elements and control gene expression.