Placenta: an old organ with new functions

Abstract

The transition from oviparity to viviparity and the establishment of feto-maternal communications introduced the placenta as the major anatomical site to provide nutrients, gases, and hormones to the developing fetus. The placenta has endocrine functions, orchestrates maternal adaptations to pregnancy at different periods of pregnancy, and acts as a selective barrier to minimize exposure of developing fetus to xenobiotics, pathogens, and parasites. Despite the fact that this ancient organ is central for establishment of a normal pregnancy in eutherians, the placenta remains one of the least studied organs. The first step of pregnancy, embryo implantation, is finely regulated by the trophoectoderm, the precursor of all trophoblast cells. There is a bidirectional communication between placenta and endometrium leading to decidualization, a critical step for maintenance of pregnancy. There are three-direction interactions between the placenta, maternal immune cells, and the endometrium for adaptation of endometrial immune system to the allogeneic fetus. While 65% of all systemically expressed human proteins have been found in the placenta tissues, it expresses numerous placenta-specific proteins, whose expression are dramatically changed in gestational diseases and could serve as biomarkers for early detection of gestational diseases. Surprisingly, placentation and carcinogenesis exhibit numerous shared features in metabolism and cell behavior, proteins and molecular signatures, signaling pathways, and tissue microenvironment, which proposes the concept of "cancer as ectopic trophoblastic cells". By extensive researches in this novel field, a handful of cancer biomarkers has been discovered. This review paper, which has been inspired in part by our extensive experiences during the past couple of years, highlights new aspects of placental functions with emphasis on its immunomodulatory role in establishment of a successful pregnancy and on a potential link between placentation and carcinogenesis.

Keywords: biomarker; cancer; embryo implantation; immunomodulation; placenta; pregnancy; proteins.

Figure 1

Structural diversity of placentas in mammals: Diffuse placentas have a uniform distribution of chorionic villi covering the chorion’s surface and are seen in horses and pigs. Cotyledonary placentas have numerous button-like structures called cotyledon that join together using vascularized intervening areas to form placentome. This type of structure is seen in sheep, goat, and cattle. Zonary placentas are like a belt created around the chorionic sac and are seen in carnivores like dogs, cats, and seals, omnivores like bears, and herbivores like elephants. Discoidal placentas form disc-like structures and this placental structure is seen in rodents and primates like humans.

Figure 2

Classification of placentas based on cell layers comprising the maternal-fetal interface. In epitheliochorial placentation, as seen in cow, horse, and ruminants, the least intimate interactions occur between fetal tissue and maternal blood since a barrier containing maternal vascular endothelium and uterine epithelium exists. In endotheliochorial placentation, as seen in dogs and cats, trophoblasts invade the uterine epithelium and contact with maternal endothelium. In hemochorial placentation, as seen in primates and humans, the most intimate contact occurs between fetal trophoblasts and maternal circulation since both the epithelium and endothelium degrade and trophoblasts are soaked in the maternal blood.

Figure 3

Triad interactions between trophoblast, decidual stromal cells and immune cells. Following implantation, the placental cytotrophoblasts in anchoring villi fuse together to form multinucleated syncitiotrophoblasts, which further differentiated to invasive extravillous trophoblasts (EVTs). The EVTs then invade the uterine tissues up to inner third of the myometrium. Some of the EVTs replace the endothelial cells and are called endovascular cytotrophoblasts (eCTBs). Secreted products from the invaded trophoblasts then modulate the function of endometrial stromal and immune cells. For example, Profilin-1 (PFN1) secreted from trophoblasts enhances the differentiation of endometrial stromal cells (EnSCs) into the epitheloid secretory decidual stromal cells (DSCs) in a process called decidualization through the action of estrogen (E2), progesterone (P4) and cyclic adenosine monophosphate (cAMP). Prolactin (PRL) is an important secreted product of DSCs and increases the production of PFN1 by trophoblasts. DSCs are master regulator of endometrial immune cells and help the function and survival of uterine natural killer cells (uNK), the most frequent immune cells in endometrium, by producing IL-15. The uNKs then produce factors such as IFN-γ, IL-18, Galectin-1, and VEGF to induce a tolerogenic phenotype in dendritic cells (DCs). Tolerogenic DCs are responsible for induction of regulatory T cells (Tregs) to maintain a pregnancy- friendly environment in the endometrium. These Tregs can also be induced by macrophages (MQs) under the influence of soluble products secreted from trophoblasts. Trophoblasts can directly induce Tregs using indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan. The available in vitro data has shown that the immune cells like uNKs can enhance the migration of trophoblasts through the secretion of chemokines. Hence, interaction between trophoblasts, EnSCs and uterine immune cells form the endometrial environment, in which each cell type modulate the function of the others. GM-CSF, Granulocyte-macrophage colony stimulating factor; XCL1, X-C motif chemokine ligand 1; IL, Interleukin; IFN, Interferon; Gal1, Galectin 1; VEGF, Vascular endothelial growth factor; TGF, Transforming growth factor; PGE2, Prostaglandin E2.

Figure 4

Gene Ontology enrichment analysis of the genes commonly expressed in cancer and placenta. The dot plot shows the top enrichment terms for the markers with a shared expression between the placenta and tumor cells. The color of each dot indicates the enrichment P value and the x-axis shows the enrichment fold. Each part points to one of the GO sections; BP, Biological Processes; CC, Cellular Component; MF, Molecular Function.