**5. The Decidua as an Anatomically Distinct Autocrine**/**Paracrine Organ**

The decidua is the maternal tissue most intimately associated with the fetoplacental unit and serves a critical role as an endocrine and immunological organ. The process of implantation/placentation results in the formation of three decidual regions, which are anatomically and functionally distinct. This review focuses on that region that underlies the placenta, known as the decidua basalis (or decidua placentalis) (Figure 1).

The endometrium/decidua is a complex, dynamic, heterogeneous tissue made up of multiple cell types. Moreover, its cellular composition changes in a predictable fashion during the menstrual cycle and throughout the course of pregnancy in response to changes in systemic and local hormones. These cellular changes have been reviewed in detail elsewhere [17,31–37]. Importantly, the endometrium/decidua is rich in immune cells, particularly uNK cells and macrophages, which originate in the bone marrow and track selectively via the bloodstream to the uterine lining. In the first 20 weeks of pregnancy, uNK cells and macrophages play a critical role in mediating the process of

spiral artery transformation by inducing initial structural changes, secreting a number of cytokines and chemokines, and promoting the actions of EVCTs [38–40]. They also protect against placental infection [41,42]. Another distinct and functionally important group of cells comprises the decidual stromal fibroblast cells (DSCs), which make up 10–30% of decidual cells in the first trimester and up to 60–70% of cells in term decidua (discussed below). *Int. J. Mol. Sci.* **2020**, *21*, x FOR PEER REVIEW 4 of 20

**Figure 1.** Anatomic arrangement of the decidua. Three anatomically and functionally discrete regions of the decidua are defined based on their relationship to the fetoplacental unit. The decidua basalis (or decidua placentalis) lies directly below the placenta. The decidua capsularis covers (encapsulates) the developing embryo as it grows and expands into the uterine cavity. The decidua parietalis (or decidua vera) lines the uterus remote from the placenta. A virtual space exists between the decidua capsularis and decidua parietalis until about 15–16 weeks of gestation, at which point **Figure 1.** Anatomic arrangement of the decidua. Three anatomically and functionally discrete regions of the decidua are defined based on their relationship to the fetoplacental unit. The decidua basalis (or decidua placentalis) lies directly below the placenta. The decidua capsularis covers (encapsulates) the developing embryo as it grows and expands into the uterine cavity. The decidua parietalis (or decidua vera) lines the uterus remote from the placenta. A virtual space exists between the decidua capsularis and decidua parietalis until about 15–16 weeks of gestation, at which point these two tissues come together and fuse.

#### these two tissues come together and fuse. **6. Endometrial Decidualization**

cytokines and chemokines, and promoting the actions of EVCTs [38–40]. They also protect against placental infection [41,42]. Another distinct and functionally important group of cells comprises the decidual stromal fibroblast cells (DSCs), which make up 10–30% of decidual cells in the first trimester and up to 60–70% of cells in term decidua (discussed below). **6. Endometrial Decidualization**  Decidualization refers to the functional and morphological changes that occur within the endometrium to form the decidual lining into which the blastocyst implants. These changes include the recruitment of leukocytes and, importantly, the differentiation of endometrial stromal fibroblast cells (ESCs) into DSCs. It is the ability of ESCs to differentiate into this alternative cell state that appears to be the key element in the decidual transformation. DSCs are not simply modified ESCs; Decidualization refers to the functional and morphological changes that occur within the endometrium to form the decidual lining into which the blastocyst implants. These changes include the recruitment of leukocytes and, importantly, the differentiation of endometrial stromal fibroblast cells (ESCs) into DSCs. It is the ability of ESCs to differentiate into this alternative cell state that appears to be the key element in the decidual transformation. DSCs are not simply modified ESCs; they are a distinct cell type resulting from terminal differentiation and the genetic reprogramming of ESCs. This reprogramming includes the downregulation of genes involved in the pro- inflammatory response and in resisting tissue invasion along with increased expression of genes that promote cellular proliferation, foster tolerance, and facilitate tissue invasion (discussed below). DSCs originated early in the stem lineage of placental mammals [43,44] and their evolution coincided precisely in evolutionary history with the appearance of invasive placentation [11,45].

#### they are a distinct cell type resulting from terminal differentiation and the genetic reprogramming of **7. Evolution of the Decidua**

ESCs. This reprogramming includes the downregulation of genes involved in the pro- inflammatory response and in resisting tissue invasion along with increased expression of genes that promote cellular proliferation, foster tolerance, and facilitate tissue invasion (discussed below). DSCs originated early in the stem lineage of placental mammals [43,44] and their evolution coincided precisely in evolutionary history with the appearance of invasive placentation [11,45]. **7. Evolution of the Decidua**  Decidualization is widespread among eutherian mammals and is perhaps best understood as a maternal solution to accommodate the invasive trophoblast. However, the presence of trophoblast Decidualization is widespread among eutherian mammals and is perhaps best understood as a maternal solution to accommodate the invasive trophoblast. However, the presence of trophoblast within the uterine cavity does not always result in invasive placentation. In some placental mammals, most notably in hoofed animals such as the pig, placentation is superficial despite the fact that trophoblast cells retain the ability to invade ectopically [46]. Such species evolved an alternative and yet equally successful strategy to tolerate the presence of the hemi-allogeneic fetal allograft, namely maternal resistance to invasion, resulting in non-invasive placentation and the lack of endometrial decidualization. The fact that different mammalian viviparous species have evolved alternative

namely maternal resistance to invasion, resulting in non-invasive placentation and the lack of endometrial decidualization. The fact that different mammalian viviparous species have evolved

within the uterine cavity does not always result in invasive placentation. In some placental

solutions to the challenge of invading trophoblast highlights the important role that the maternal–fetal interaction plays in determining the resulting pregnancy phenotype, both across and within species. The functional importance of decidualization in human pregnancy is incompletely understood, but it appears to play a critical role in facilitating the active embedding of the conceptus [47], in the negative selection of nonviable embryos [48], in determining the optimal window of implantation [49,50], and in uterine hemostasis [51,52]. Proper decidualization controls conception and the course of pregnancy and is a critical determinant of pregnancy success in humans [2]. In non-menstruating species, the embryo controls this process by delaying implantation [53].
