Function and control of human invasive trophoblast subtypes: Intrinsic vs. maternal control

Abstract

The establishment of a functional placenta is pivotal for normal fetal development and the maintenance of pregnancy. In the course of early placentation, trophoblast precursors differentiate into highly invasive trophoblast subtypes. These cells, referred to as extravillous trophoblasts (EVTs), penetrate the maternal uterus reaching as far as the inner third of the myometrium. One of the most fundamental functions of EVTs is the transformation of spiral arteries to establish the uteroplacental blood circulation assuring an adequate nutrient and gas supply to the developing fetus. To achieve this, specialized EVT subpopulations interact with maternal immune cells, provoke elastolysis in the arterial wall and replace the endothelial cells lining the spiral arteries to induce intraluminal vascular remodeling. These and other trophoblast-mediated processes are tightly controlled by paracrine signals from the maternal decidua and furthermore underlie an intrinsic cell-type specific program. Various severe pregnancy complications such as preeclampsia or intrauterine growth retardation are associated with abnormal EVT function, shallow invasion, and decreased blood flow to the placenta. Hence a better understanding of human trophoblast invasion seems mandatory to improve therapeutic intervention. This approach, however, requires a profound knowledge of the human placenta, its various trophoblast subtypes and in particular a better understanding of the regulatory network that controls the invasive phenotype of EVTs.

Keywords: EVT; decidua; invasion; placenta; preeclampsia; trophoblast.

Figure 1.

Human trophoblast invasion. (A) The placenta connects the fetus to the uterine wall and establishes a vascular connection between mother and child. The placenta is structured as villous tree and is in direct contact with maternal blood and, thus referred to as hemochorial. The site where the placenta comes in direct contact with the maternal decidua is called the fetal-maternal interface. (B) During early pregnancy, vCTBs fuse to form multinucleated STs, which surround the placental villus. STs transport nutrients and gases from the maternal to the fetal circulation and represent the major endocrine unit of the placenta by secreting hormones such as chorionic gonadotropin, placental growth hormone or placental lactogen. AV form cell columns that attach to the maternal decidua and give rise to the EVT lineage. Invasive EVTs can be divided into iCTBs, which invade the decidual stroma and become terminally differentiated multinucleated GCs, or eCTBs. (i) The latter colonise the lumen of uterine spiral arteries and together with iCTBs, macrophages and uNK cells convert these vessels into larger conduits to guarantee adequate blood flow to the growing fetus. (ii) Various decidual cell types such as macrophages, uNK cells and decidual stromal cells interact with the interstitial cytotrophoblasts in order to control iCTB invasion in an in a spatio-temporal manner. (iii) In addition, iCTBs invade and replace the epithelium of endometrial glands. AV, anchoring villus; CC, cell column; EVT, extravillous cytotrophoblast; eCTB, endovascular cytotrophoblast; iCTB, interstitial cytotrophoblast; SA, spiral artery; ST, syncytiotrophoblast; uNK, uterine natural killer cell.