Trophoblast stem cells, trophoblast invasion, and organoids - advancements in gynecology.

The human placenta serves as a vital barrier between the mother and the developing fetus during pregnancy. A defect in the early development of the placenta is associated with severe pregnancy disorders. Despite its complex development, various molecular processes control placental development, and the specialization of trophoblast cells is still not fully understood. One primary obstacle is the lack of suitable cell model systems. Traditional two-dimensional (2D) cell cultures fail to mimic in vivo conditions and do not capture the intricate intercellular interactions vital for studying placental development. However, three-dimensional (3D) organoid models derived from stem cells that replicate natural cell organization and architecture have greatly improved our understanding of trophoblast behavior and its medicinal applications. Organoids with relevant phenotypes provide a valuable platform to model both placental physiology and pathology, including the modeling of placental disorders. They hold great promise for personalized medicine, improved diagnostics, and the evaluation of pharmaceutical drug efficacy and safety. This article provides a concise overview of trophoblast stem cells, trophoblast invasion, and the evolving role of organoids in gynecology.

Immunological regulation and the role of autophagy in preeclampsia.

Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous trophoblasts invade the decidua and uterine myometrium, facing maternal immune cells, which participate in the immune suppression of paternal and fetal antigens. Regulatory T cells will likely increase in response to a specific antigen before and during early pregnancy. Insufficient expansion of antigen-specific Treg cells, which possess the same T cell receptor, is associated with the pathophysiology of preeclampsia, suggesting sterile systemic inflammation. Autophagy is involved in reducing inflammation through the degradation of inflammasomes and in the differentiation and function of regulatory T cells. Autophagy dysregulation induces protein aggregation in trophoblasts, resulting in placental dysfunction. In this review, we discuss the role of regulatory T cells in normal pregnancies. In addition, we discuss the association between autophagy and regulatory T cells in the development of preeclampsia based on reports on the role of autophagy in autoimmune diseases.

Establishment and comparison of human term placenta-derived trophoblast cells†.

Research on the biology of fetal-maternal barriers has been limited by access to physiologically relevant cells, including trophoblast cells. In this study, we describe the development of a human term placenta-derived cytotrophoblast immortalized cell line (hPTCCTB) derived from the basal plate. Human-term placenta-derived cytotrophoblast immortalized cell line cells are comparable to their primary cells of origin in terms of morphology, marker expression, and functional responses. We demonstrate that these can transform into syncytiotrophoblast and extravillous trophoblasts. We also compared the hPTCCTB cells to immortalized chorionic trophoblasts (hFM-CTC), trophoblasts of the chorionic plate, and BeWo cells, choriocarcinoma cell lines of conventional use. Human-term placenta-derived cytotrophoblast immortalized cell line and hFM-CTCs displayed more similarity to each other than to BeWos, but these differ in syncytialization ability. Overall, this study (1) demonstrates that the immortalized hPTCCTB generated are cells of higher physiological relevance and (2) provides a look into the distinction between the spatially distinct placental and fetal barrier trophoblasts cells, hPTCCTB and hFM-CTC, respectively.

VGLL1 cooperates with TEAD4 to control human trophectoderm lineage specification.

In contrast to rodents, the mechanisms underlying human trophectoderm and early placenta specification are understudied due to ethical barriers and the scarcity of embryos. Recent reports have shown that human pluripotent stem cells (PSCs) can differentiate into trophectoderm (TE)-like cells (TELCs) and trophoblast stem cells (TSCs), offering a valuable in vitro model to study early placenta specification. Here, we demonstrate that the VGLL1 (vestigial-like family member 1), which is highly expressed during human and non-human primate TE specification in vivo but is negligibly expressed in mouse, is a critical regulator of cell fate determination and self-renewal in human TELCs and TSCs derived from naïve PSCs. Mechanistically, VGLL1 partners with the transcription factor TEAD4 (TEA domain transcription factor 4) to regulate chromatin accessibility at target gene loci through histone acetylation and acts in cooperation with GATA3 and TFAP2C. Our work is relevant to understand primate early embryogenesis and how it differs from other mammalian species.

Implications for miR-339-5p regulation of trophoblast proliferation and migration in placentas associated with porcine intrauterine growth retardation using integrated transcriptome sequencing analysis.

Placental dysfunction is considered as one of the main etiologies of fetal intrauterine growth retardation (IUGR). MicroRNAs (miRNAs) have been demonstrated to be a vital epigenetic modification involved in regulating the placental function and pregnancy outcomes in mammals. However, the mechanisms underlying placenta-specific miRNAs involved in the occurrence and development of pig IUGR remain unclear. In this work, we compared the placental morphologies of piglets with IUGR and normal birth weight (NBW) by using histomorphological analysis and performed a miRNA-mRNA integrative analysis of the gene expression profiles of IUGR and NBW placentas through RNA sequencing. We also investigated the role of differentially expressed ssc-miR-339-5p/GRIK3 through an in vitro experiment on porcine trophoblast cells (PTr2). IUGR piglets had significantly lower birth weight, placental weight, placental efficiency, and placental villus and capillary densities compared with the NBW piglets (P < 0.05). A total of 81 differentially expressed miRNAs and 726 differentially expressed genes in the placentas were screened out between the IUGR and NBW groups. The miRNA-mRNA interaction networks revealed the key core miRNA (ssc-miR-339-5p) and its corresponding target genes. Subsequently, we found that upregulation of ssc-miR-339-5p significantly inhibited the migration and proliferation of PTr2 cells (P < 0.05). The dual-luciferase reporter system showed that GRIK3 was the target gene of ssc-miR-339-5p, and the transcription level of GRIK3 may be negatively regulated by ssc-miR-339-5p. Additionally, overexpression of ssc-miR-339-5p significantly increased (P < 0.05) the mRNA expression levels of genes involved in the cytokine-cytokine receptor interaction pathway. These results indicate that ssc-miR-339-5p may affect the migration and proliferation of trophoblast cells by regulating the expression of GRIK3 and altering the placental inflammatory response, resulting in a suboptimal morphology and function of the placenta and the development of pig IUGR.

Mouse Trophoblast Cells Have Attenuated Responses to TNF-α and IFN-γ and Can Avoid Synergic Cytotoxicity of the Two Cytokines.

TNF-α and IFN-γ are two inflammatory cytokines that play critical roles in immune responses, but they can also negatively affect cell proliferation and viability. In particular, the combination of the two cytokines (TNF-α/IFN-γ) synergistically causes cytotoxicity in many cell types. We recently reported that mouse embryonic stem cells (ESCs) isolated from the blastocyst stage embryo do not respond to TNF-α and have limited response to IFN-γ, thereby avoiding TNF-α/IFN-γ cytotoxicity. The current study expanded our investigation to mouse trophoblast stem cells (TSCs) and their differentiated trophoblasts (TSC-TBs), the precursors and the differentiated cells of the placenta, respectively. In this study, we report that the combination of TNF-α/IFN-γ does not show the cytotoxicity to TSCs and TSC-TBs that otherwise effectively kills fibroblasts, similar to ESCs. Although ESCs, TSCs, and TSC-TBs are dramatically different in their growth rate, morphology, and physiological functions, they nevertheless share a similarity in being able to avoid TNF-α/IFN-γ cytotoxicity. We propose that this unique immune property may serve as a protective mechanism that limits cytokine cytotoxicity in the blastocyst. With molecular and cellular approaches and genome-wide transcriptomic analysis, we have demonstrated that the attenuated NF-κB and STAT1 transcription activation is a limiting factor that restricts the effect of TNF-α/IFN-γ on TSCs and TSC-TBs.

Down-regulated Wnt7a and GPR124 in early-onset preeclampsia placentas reduce invasion and migration of trophoblast cells.

OBJECTIVES: Preeclampsia (PE) is a disease specific to pregnancy that causes 9-10 % of maternal deaths. Early-onset PE (<34 weeks' gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a's role in trophoblast cells. METHODS: Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation. RESULTS: In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=-0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis. CONCLUSIONS: Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction.

Downregulation of PGRMC1 accelerates differentiation and fusion of a human trophoblast cell line.

Mononuclear cytotrophoblasts (CTs) differentiate and fuse to form multinuclear syncytiotrophoblasts (STs), which produce human chorionic gonadotropin (hCG) and progesterone to maintain pregnancy. Impaired differentiation and fusion of CTs to form STs are associated with hypertensive disorders of pregnancy and fetal growth restriction. Progesterone receptor membrane component 1 (PGRMC1) is a multifunctional single transmembrane heme-binding protein. We previously demonstrated that downregulation of PGRMC1 promotes endometrial stromal cell differentiation (decidualization). Here, we explored the role of PGRMC1 in trophoblast differentiation and fusion. PGRMC1 expression was lower in STs than in CTs of first-trimester placental tissues. PGRMC1 expression in BeWo cells (a trophoblast-derived choriocarcinoma cell line) decreased upon dibutyryl-cAMP (db-cAMP)-induced differentiation. Both inhibition and knockdown of PGRMC1 stimulated hCG production in the presence of db-cAMP. Furthermore, a quantitative cell fusion assay we developed revealed that inhibition and knockdown of PGRMC1 enhanced db-cAMP-stimulated cell fusion. Peroxisome proliferator-activated receptor γ (PPARγ) agonists decreased PGRMC1 expression and stimulated the cell fusion in BeWo cells. These findings suggest that downregulation of PGRMC1 expression in part through activation of PPARγ during trophoblast differentiation promotes hCG production and cell fusion for formation and maintenance of placental villi during pregnancy.

Folate-depletion alters mouse trophoblast stem cell regulation in vitro.

Maternal folate deficiency increases risk of congenital malformations, yet its effect on placenta development is unclear. Here, we investigated how folate-depleted culture medium affects the developmental potential of mouse trophoblast stem cells (TSCs). When cultured in stem cell conditions, TSC viability was unaffected by folate depletion, but ectopic differentiation of trophoblast cell subtypes occurred. When cultured in conditions that promote differentiation, folate-depleted TSCs were driven towards a syncytiotrophoblast cell fate potentially at the expense of other lineages. Additionally, trophoblast giant cell nuclei were small implicating folate in the regulation of endoreduplication. Therefore, dietary folate intake likely promotes trophoblast development.

Validation of the Sw71-spheroid model with primary trophoblast cells.

PROBLEM: Human implantation is a limiting factor for the success of natural and IVF reproduction since about 60% of pregnancy losses occur in the peri-implantation period. The in vitro modeling of human implantation challenges the researchers in accurate recreation of the complex in vivo differentiation and function of human blastocyst in the peri-implantation period. In previous studies, we constructed Sw71-spheroid models, which like human blastocyst undergo compactization, attaches to the endometrial epithelium, invade, and migrate. The aim of this study was to validate the trophoblast Sw71-spheroid model with primary trophoblast cells, derived from healthy women in early pregnancy. METHOD OF STUDY: We performed a direct comparison of Sw71-spheroid model with placenta-derived primary trophoblasts regarding their hybrid phenotype and HLA status, as well as the ability to generate spheroids able to migrate and invade. From the primary trophoblast cells, isolated by mild enzymatic treatment and Percoll gradient separation, were generated long-lived clones, which phenotype was assessed by FACS and immunocytochemistry. RESULTS: Our results showed that cultured primary trophoblasts have the EVT phenotype (Vim+/CK7+/HLA-C+/HLA-G+), like Sw71 cells. In both 3D culture settings, we obtained stable, round-shaped, multilayered spheroids. Although constructed from the same number of cells, the primary trophoblast spheroids were smaller. The primary trophoblast spheroids migrate successfully, and in term of invasion are equally potent but less stable as compared to Sw71 spheroids. CONCLUSIONS: The Sw71 cell line and cultured native trophoblast cells are interchangeable regarding their EVT phenotype (HLA-C+/HLA-G+/Vim+/CK7+). The blastocyst-like spheroids sourced by both types of cells differentiate in the same time frame and function similarly. We strongly advise the use of Sw71 spheroids as blastocyst surrogate for observation on trophectoderm differentiation and function during early human implantation.

A spatially resolved timeline of the human maternal-fetal interface.

Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR)1-3. However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.

Cell-free fetal DNA impairs trophoblast migration in a TLR9-dependent manner and can be reversed by hydroxychloroquine.

Growing evidence suggests a relationship between elevated circulating placental-derived cell-free fetal DNA (cffDNA) and preeclampsia. Hypomethylation of CpG motifs, a hallmark of cffDNA, allows it to activate Toll-like receptor 9 (TLR9). Using an in vitro human first trimester extravillous trophoblast cell model, we sought to determine if trophoblast-derived cffDNA and ODN 2216, a synthetic unmethylated CpG oligodeoxynucleotide, directly impacted spontaneous trophoblast migration. The role of the DNA sensors TLR9, AIM2, and cGAS was assessed using the inhibitor A151. To test whether any effects could be reversed by therapeutic agents, trophoblasts were treated with or without cffDNA or ODN 2216 with or without aspirin (ASA; a known cGAS inhibitor), aspirin-triggered lipoxin (ATL), or hydroxychloroquine (HCQ; a known TLR9 inhibitor). Trophoblast-derived cffDNA and ODN 2216 reduced trophoblast migration without affecting cell viability. Reduced trophoblast migration in response to cffDNA or ODN 2216 was reversed by A151. cffDNA inhibition of trophoblast migration was reversed by HCQ, while ASA or ATL had no effect. In contrast ODN 2216 inhibition of trophoblast migration was reversed by ASA, ATL and HCQ. Our findings suggest that cffDNA can exert a local effect on placental function by impairing trophoblast migration through activation of innate immune DNA sensors. HCQ, a known TLR9 inhibitor, reversed the effects of cffDNA on trophoblast migration. Greater insights into the molecular underpinnings of how cffDNA impacts placentation can aid in our understanding of the pathogenesis of preeclampsia, and in the development of novel therapeutic approaches for preeclampsia therapy.

Barriers to progress in pregnancy research: How can we break through?

Healthy pregnancies are fundamental to healthy populations, but very few therapies to improve pregnancy outcomes are available. Fundamental concepts-for example, placentation or the mechanisms that control the onset of labor-remain understudied and incompletely understood. A key issue is that research efforts must capture the complexity of the tripartite maternal-placental-fetal system, the dynamics of which change throughout gestation. Studying pregnancy disorders is complicated by the difficulty of creating maternal-placental-fetal interfaces in vitro and the uncertain relevance of animal models to human pregnancy. However, newer approaches include trophoblast organoids to model the developing placenta and integrated data-science approaches to study longer-term outcomes. These approaches provide insights into the physiology of healthy pregnancy, which is the first step to identifying therapeutic targets in pregnancy disorders.

Endogenous retrovirus-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization.

Endogenous retroviruses (ERVs) have been proposed as a driving force for the evolution of the mammalian placenta, however, the contribution of ERVs to placental development and the underlying regulatory mechanism remain largely elusive. A key process of placental development is the formation of multinucleated syncytiotrophoblasts (STBs) in direct contact with maternal blood, through which constitutes the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. We delineate that ERVs profoundly rewire the transcriptional program of trophoblast syncytialization. Here, we first determined the dynamic landscape of bivalent ERV-derived enhancers with dual occupancy of H3K27ac and H3K9me3 in human trophoblast stem cells (hTSCs). We further demonstrated that enhancers overlapping several ERV families tend to exhibit increased H3K27ac and reduced H3K9me3 occupancy in STBs relative to hTSCs. Particularly, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of genes important for STB formation. Importantly, deletions of MER50 elements adjacent to several STB genes, including MFSD2A and TNFAIP2, significantly attenuated their expression concomitant to compromised syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional networks accounting for human trophoblast syncytialization, which sheds light on a novel ERV-mediated regulatory mechanism underlying placental development.

Spatial multiomics map of trophoblast development in early pregnancy.

The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels1. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia2. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids3,4 and trophoblast stem cells5. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.

Hsa_circ_0001326 inhibited the proliferation, migration, and invasion of trophoblast cells via miR-145-5p/TGFB2 axis.

PROBLEM: Preeclampsia (PE) is an obstetric disease involving multiple systems, which account for maternal and fetal complications and increased mortality. Circular RNAs (circRNAs) were recently deemed to associate with the pathogenesis of PE. This study aims to clarify the correlation between circRNA hsa_circ_0001326 and PE and explore its biological function in PE. METHOD OF STUDY: The expression of hsa_circ_0001326 in PE placentas was detected by real-time quantitative PCR (qRT-PCR). After overexpressing or inhibiting hsa_circ_0001326 in trophoblast cells, the cell growth, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8) and transwell assays. Western blot assay was applied to detect the epithelial-mesenchymal transition (EMT) proteins, E-cadherin and Vimentin. Furthermore, a dual-luciferase reporter assay was applied to verify the binding sites of hsa_circ_0001326, miR-145-5p, and transforming growth factor beta 2 (TGFB2). RESULTS: Hsa_circ_0001326 was found to be higher expressed in PE placentas than in normal placentas. Furthermore, hsa_circ_0001326 played a negative regulating role in trophoblast cell viability, migration, and invasion. Overexpression of hsa_circ_0001326 inhibited the viability, migration, and invasion of trophoblast cells, while inhibition of hsa_circ_0001326 showed opposite effects. Mechanistically, hsa_circ_0001326 sponged miR-145-5p to elevate TGFB2 expression in trophoblast cells. CONCLUSION: This study provided evidence that the up-regulated hsa_circ_0001326 in PE restrained trophoblast cells proliferation, migration, and invasion by sponging miR-145-5p to elevate TGFB2 expression. Our results might provide a novel insight into the role of hsa_circ_0001326 in the pathogenesis of PE.

Origins of abnormal placentation: why maternal veins must not be forgotten.

The importance of uterine microvascular adaptations during placentation in pregnancy has been well established for decades. Inadequate dilatation of spiral arteries is associated with gestational complications, such as preeclampsia and/or intrauterine growth restriction. More recently, it has become clear that trophoblast cells invade and adapt decidual veins and lymphatic vessels 1 month before spiral arteries become patent and before intervillous space perfusion starts. Normal intervillous space hemodynamics is characterized by high volume flow at low velocity and pressure in the interseptal compartments surrounding the chorionic villi, hereby facilitating efficient maternal-fetal exchange. In case of shallow decidual vein dilatation, intervillous arterial supply exceeds venous drainage. This will cause congestion in the interseptal compartments with subsequently reduced perfusion and increased pressure. An efficient mechanism to counteract venous congestion and safeguard the viability of the conceptus is by reducing arterial inflow via shallow dilatation of the spiral arteries. This review made the case for intervillous space congestion as an unexplored trigger for inadequate spiral artery dilatation during the placentation process, eventually leading to abnormal systemic circulatory dysfunctions. An abnormal maternal venous function can result from an abnormal maternal immune response to paternal antigens with an imbalanced release of vasoactive mediators or can exist before conception. To get the full picture of abnormal placentation, maternal veins must not be forgotten.

Resveratrol alleviates preeclampsia-like symptoms in rats through a mechanism involving the miR-363-3p/PEDF/VEGF axis.

Preeclampsia (PE) is a hypertension-associated disease, and resveratrol (RES) is a polyphenol recognized to present beneficial effects in cardiovascular disease including hypertension. Recently, attentions have come to the therapeutic effect of RES in PE, but the underlying molecular mechanisms remain largely unknown. This study sought to delineate the mechanistic basis regarding bioinformatically identified miR-363-3p/PEDF/VEGF axis for RES treatment in PE. PE-like symptoms were induced in vivo in Sprague-Dawley rats by intraperitoneal injection with Ng-nitro-L-arginine methyl ester (L-NAME), and hypoxia was induced in vitro in trophoblasts by CoCl2. Accordingly, RES was found to enhance viability, migration, angiogenesis, and to repress the apoptosis of hypoxic trophoblasts in vitro. Furthermore, in vivo experiments noted that RES alleviated placental injury and promoted angiogenesis in rats with PE-like symptoms in vivo by increasing VEGF via promoting miR-363-3p-mediated PEDF suppression. Collectively, RES ameliorates PE by upregulating VEGF through miR-363-3p-mediated PEDF downregulation, the mechanism of which may be of promising significance to augment RES efficacy in PE treatment.

The Role of Interferon (IFN)-γ in Extravillous Trophoblast Cell (EVT) Invasion and Preeclampsia Progression.

The involvement of the immune system in pregnancy is a controversial subject. The functions of T helper (Th) 1 and Th2 cells have been proposed, that Th1 cytokines promoting allograft rejection may impair pregnancy, whereas Th2-type cytokines suppressing Th1 responses improve allograft tolerance and hence embryonic survival. Maternal-fetal tolerance begins in the uterus; therefore, optimal adaptation to the fetus is the result of a complex interference. The invasion of extravillous trophoblast cells (EVTs) into the decidua and the inner third of the myometrium is essential for a healthy pregnancy. The mechanisms that influence trophoblast invasion are unknown; however, cytokines from uterine natural killer (uNK) cells, NKT cells, macrophages, and T cells appear to be involved. All these cells are major sources of interferon gamma (IFN-γ). Recent studies have shown that IFN-γ can inhibit EVT invasion via a mechanism dependent on an increase in EVT apoptosis and a decrease in matrix metalloproteinases (MMPs). Regarding controversies in this context, this study aimed to comprehensively review the role of IFN-γ and IFN-γ-producing cells in EVT invasion, successful pregnancy, and preeclampsia.

Local immune recognition of trophoblast in early human pregnancy: controversies and questions.

The role of the maternal immune system in reproductive success in humans remains controversial. Here we focus on the events that occur in the maternal decidua during the first few weeks of human pregnancy, because this is the site at which maternal leukocytes initially interact with and can recognize fetal trophoblast cells, potentially involving allorecognition by both T cells and natural killer (NK) cells. NK cells are the dominant leukocyte population in first-trimester decidua, and genetic studies point to a role of allorecognition by uterine NK cells in establishing a boundary between the mother and the fetus. By contrast, definitive evidence that allorecognition by decidual T cells occurs during the first trimester is lacking. Thus, our view is that during the crucial period when the placenta is established, damaging T cell-mediated adaptive immune responses towards placental trophoblast are minimized, whereas NK cell allorecognition contributes to successful implantation and healthy pregnancy.