**2. Cytotrophoblast cells and placenta-derived exosomes in successful placentation and fetal development**

The successful pregnancy requires the suitable development of embryo and adequate placentation [31–33]. The appropriate placentation is based on the proper capacity of villous cytotrophoblasts to fuse and form the syncytiotrophoblast which contributes to development of placenta. Therefore, abnormal cytotrophoblast differentiation results in placental-related pregnancy diseases [34–36].

Many cytotrophoblast cell subtypes (cytotrophoblasts (CTBs), extravillous cytotrophoblasts (EVTs) and syncytiotrophoblast (STB)) with different structures and functions

#### *Perspective Chapter: Role of Cytotrophoblast Cells and Placenta-Derived Exosomes… DOI: http://dx.doi.org/10.5772/intechopen.108335*

are involved in placentation [37, 38]. After implantation of the zygote, trophoblast cells develop from the outer cells which form the wall of the blastocyst, and differentiate into either villous or extravillous trophoblast cells [38]. The STBs are the outer lining of the placenta; fulfill a vast range of role including gas and nutrient exchange between mother and fetus. The trophoblast cell subtypes in addition to secreting hormones and proteins, physically protect the fetus from pathogens [39, 40]. EVTs are invasive trophoblast cells that are important for implantation of the placenta and the development of the fetus [41–43]. Many pregnancy diseases such as PE and intrauterine growth retardation (IUGR) are the consequences of defective placentation [34–36]. Therefore, the normal development of the placenta is based on complex mechanisms of proliferation and differentiation of trophoblast cells [44, 45]. Many factors (e.g., interferon-induced transmembrane protein 1 (IFITM) and Storkhead box 1 (STOX1) SNPs, Syncytins, and factors released by placenta soluble fms-like tyrosine kinase-1 (sFlt-1), placenta growth factor (PlGF), transforming growth factor-β (TGF-β)) govern the regulation of cytotrophoblast cell differentiation showing their potential use as biomarker [46–48].

Placental syncytialization is maintained throughout pregnancy by the fusion of adjacent CTBs [49, 50] and is important for successful pregnancy [49, 51–54]. Syncytins are important players during syncytialization and *Vargas et al.* and Lokossou et al. indicated that insufficient Syncytin-2 (Syn-2) expression could be the potential cause of PE, shedding light on the correlation between Syn-2 level and cytotrophoblasts fusion [46, 50, 55, 56].

In recent years, the role of exosomes in the development of the placenta has become more and more precise [46, 56, 57]. These microvesicles with diameters of 20–130 nm are extracellular secreted vesicles and are involved in cell-to-cell communication [58]. They, therefore, affect cytotrophoblast differentiation and immune regulation, especially during pregnancy [58, 59]. Exosomes are secreted by most cells and embedded in various substances including proteins [46, 56, 60, 61], mRNA and miRNA [62], and DNA [63]. They can be transported to distant organs and are thought to modify various cells and organ functions [56, 64, 65]. SDE which embedded placenta-specific molecules, including Syn-2, were involved in CTB fusion [55], embryo implantation *via* the promotion of T regulatory cells, suppression of Nuclear Factor-kB signaling pathway [66] and thereby in immune reaction and inflammatory response [56]. Secreted exosomes from the placenta into the systemic circulation lead in multisystemic organ damage, in patients with PE [67]. Reduction of Syn-2 levels in exosomes is suggested to be an early biomarker of PE [46, 60]. Indeed, the identification of women at high risk of PE before its onset is especially a challenge. Exosomes miRNA pattern also appears to be used for early PE diagnosis [68]. SDE in preeclamptic placentas are thought to embed high concentrations of PE-specific contents, resulting in unfavorable microenvironments for the invasion of EVTs and the remodeling of spiral arteries for adequate placentation [46, 57, 63, 66–72].

Nowadays, evidence suggests that disruption of placentation characterizes the pathogenesis of PE [55, 73]. Indeed, STB-derived exosomes are found in maternal circulation [72], and affected endothelial function due to their abundant sFlt-1 and soluble endoglin (sEng) content [69]. These vesicles are also endowed with immune regulation capacities during pregnancy due to Syn-2 embedded in exosomes [56].

Placental exosomes are therefore able to deliver many molecules including proteins around CTB, inducing a particular environment that affects placenta and fetal growth.

The immunosuppressive protein derived from human endogenous retrovirus sequences, Sync-2. plays a leading role in placenta formation [49, 50]. For several years our knowledge has grown on PE and placental exosomes. We have demonstrated the role of Sync-2 in placentation and in T cell immunosuppression [56, 60, 74] during normal pregnancy and PE, suggesting that Sync-2 could be used as an early biomarker of PE. Our recent data from Benin show a gradual diminution, between 7 and 10 weeks of pregnancy (WP), in the incorporation of Sync-2 in serum-derived exosomes from women who had developed a PE later during their pregnancy in comparison to samples from women with normal pregnancy [46]. Sync-2 through its immunosuppressive domain might contribute greatly to creating an immunosuppressive environment. This environment is reinforced and maintained by other factors such as Bregs. This immunosuppressive environment is essential at the beginning of pregnancy for the allograft tolerance constituted by the fetus [75]. As we demonstrated that Sync-2 generates an immunosuppression (IS) environment, Bregs should be important to maintain the IS environment and to prevent allograft rejection. Indeed, PE is a placental and inflammatory disease and syncytiotrophoblast-derived exosomes contribute to materno-fetal immuno-tolerance [56]. Such defective placentation is thought to be caused by an abnormal CTB fusion due to defective production of Sync-2 [46, 49, 55] but also to abnormal maternal immune regulation, involving Sync-2 [56]. Many immune cells, including T cell, macrophage, natural killer, regulatory B and T cells, are also affected during PE [76]. Therefore, it will be of great importance to understand how cytotrophoblast and/or syncytiotrophoblast cells and placenta-derived exosomes contribute to PE by altering Bregs differentiation and function during human pregnancy. By demonstrating that Bregs frequency and function increase susceptibility to PE, would lead to the immediate management of pregnant women predisposed to the development of severe PE and reduce the number of resulting morbidity and deaths.
