Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment

Abstract

During placentation invasive extravillous trophoblasts (EVTs) migrate into the maternal uterus and modify its vessels. In particular, remodeling of the spiral arteries by EVTs is critical for adapting blood flow and nutrient transport to the developing fetus. Failures in this process have been noticed in different pregnancy complications such as preeclampsia, intrauterine growth restriction, stillbirth, or recurrent abortion. Upon invasion into the decidua, the endometrium of pregnancy, EVTs encounter different maternal cell types such as decidual macrophages, uterine NK (uNK) cells and stromal cells expressing a plethora of growth factors and cytokines. Here, we will summarize development of the EVT lineage, a process occurring independently of the uterine environment, and formation of its different subtypes. Further, we will discuss interactions of EVTs with arteries, veins and lymphatics and illustrate how the decidua and its different immune cells regulate EVT differentiation, invasion and survival. The present literature suggests that the decidual environment and its soluble factors critically modulate EVT function and reproductive success.

Keywords: decidual immune cells; decidual macrophages; extravillous trophoblast; placental development; trophoblast invasion; uterine natural killer cells.

Figure 1

Structure of a placental anchoring villus and its different trophoblast subtypes. Precursors, residing in the villous cytotrophoblast (vCTB) layer either differentiate into multinuclear syncytiotrophoblasts (STBs), surrounded by maternal blood, or give rise to proliferative proximal cell column trophoblasts (pCCTs) upon attachment of villi to the maternal decidua. After differentiation into distal cell column trophoblasts (dCCTs) extravillous trophoblasts (EVTs) develop, breaking through the overlying STB layer. EVTs detach from distal cell columns, migrate into the decidual stroma and the maternal spiral arteries replacing maternal endothelial cells. In the decidual stroma interstitial CTBs (iCTBs) interact with macrophages, B- and T-cells, mast cells, dendritic cells, neutrophils, decidual stromal cells, and uterine natural killer (uNK) cells. Moreover, iCTBs approach the vessel walls of spiral arteries and promote remodeling from outside. Also, veins (v), lymphatics (l) and glands (g) are invaded by these cells forming multinucleated trophoblast giant cells (GC) as an end-stage of differentiation.

Figure 2

Schematical depiction of soluble factors secreted from decidual macrophages, stromal cells, or glands. Mediators, stimulating proliferation of proximal cell column trophoblasts (pCCTs) in villous explant cultures are illustrated. dCCT, distal cell column trophoblast; STB, syncytiotrophoblast; vCTB, villous cytotrophoblast; iCTB, interstitial cytotrophoblast.

Figure 3

Expression of decidual chemokines, cytokines and other soluble mediators affecting trophoblast migration and/or invasion. Some of the depicted factors likely play numerous roles at the fetal-maternal interface including activation and maturation of immune cells, as well as decidual angiogenesis and spiral artery remodeling. EVT, extravillous trophoblast; uNK cell, uterine natural killer cell; DF, decidual fibroblast.