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Coronavirus disease 2019 (COVID-19) is a pneumonia pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1 First identified in December 2019 in an outbreak of pneumonia in Wuhan City (Hubei Province, China), COVID-19 currently affects over 210 countries and territories worldwide. 2 The World Health Organization (WHO) declared COVID-19 to be a Public Health Emergency of International Concern, 3 then a pandemic, on March 11, 2020. 4 By June 30, 2020, there had been over 10 million confirmed cases, including over 500.000 patient deaths. 2 The majority of COVID-19 patients manifest mild to moderate symptoms; approximately 15% progress to the severe form of the

ProblemEmbryo implantation depends on the interactions between the developing embryo and the maternal endometrium. Signals originating from the decidua play a critical role in the process of implantation and trophoblast invasion; however, the molecular mechanisms mediating this interaction are poorly understood. The objective of this study was to develop in vitro models that would mimic the processes of attachment, migration, and early invasion of the trophoblast.Methods of studyFirst trimester trophoblast cells (Sw.71 cells) were cultured in low attachment plates to form blastocyst‐like spheroids (BLS). Epithelial‐mesenchymal transition (EMT) characterization during BLS formation was determined by RT‐PCR and Western Blot. The two 3D in vitro culture models consist of (a) trophoblast migration: BLS cultured in suspension (b) trophoblast invasion: human endometrium stromal cells (HESC) plated in the bottom of a 96‐well plate, covered by Matrigel and BLS transferred on top. Matrigel was used to mimic the human endometrial extracellular matrix.ResultsUsing 3D cell culture systems and real‐time imaging, we are able to determine the impact of endometrial factors on trophoblast cell function. Endometrial stromal cells promote blastocyst‐like spheroid migration of trophoblast cells and invasion of the extracellular matrix.ConclusionWe report the characterization of 3D in vitro models to evaluate the interaction between endometrial cells and trophoblast during the process of migration and invasion. The models are useful tools in order to further study the molecular mechanism of embryo‐maternal uterine cells interactions.

Decidual macrophages are in close contact with trophoblast cells during placenta development, and an appropriate crosstalk between these cellular compartments is crucial for the establishment and maintenance of a healthy pregnancy. During different phases of gestation, macrophages undergo dynamic changes to adjust to the different stages of fetal development. Trophoblast‐secreted factors are considered the main modulators responsible for macrophage differentiation and function. However, the phenotype of these macrophages induced by trophoblast‐secreted factors and the factors responsible for their polarization has not been elucidated. In this study, we characterized the phenotype and function of human trophoblast‐induced macrophages. Using in vitro models, we found that human trophoblast‐educated macrophages were CD14+CD206+CD86− and presented an unusual transcriptional profile in response to TLR4/LPS activation characterized by the expression of type I IFN‐β expression. IFN‐β further enhances the constitutive production of soluble programmed cell death ligand 1 (PD‐L1) from trophoblast cells. PD‐1 blockage inhibited trophoblast‐induced macrophage differentiation. Soluble PD‐L1 (sPD‐L1) was detected in the blood of pregnant women and increased throughout the gestation. Collectively, our data suggest the existence of a regulatory circuit at the maternal fetal interface wherein IFN‐β promotes sPD‐L1 expression/secretion by trophoblast cells, which can then initiate a PD‐L1/PD‐1‐mediated macrophage polarization toward an M2 phenotype, consequently decreasing inflammation. Macrophages then maintain the expression of sPD‐L1 by the trophoblasts through IFN‐β production induced through TLR4 ligation.

Recurrent spontaneous abortion (RSA) is a growing problem worldwide. In a majority of cases, the cause remains unknown but there is increasing evidence that immunologic factors play an important role. Intravenous immunoglobulin (IVIg) therapy has been proposed to have immune modulatory effects and therefore been applicable for the treatment of patients with RSA. Although its efficacy is still controversial, several recent studies suggest that IVIg treatment may improve pregnancy outcomes. CD4 T cells and their related cytokines play an important role in maternal-fetal immune regulation, and an imbalance of Th17/Treg cell ratio has been proposed as a cause for RSA. We review the scientific evidence supporting a modulatory effect of IVIg on Th17/Treg cell balance and discuss the potential mechanisms how IVIg might enhance Treg cells function. We propose that correction of Th17/Treg cell dysregulation could be one of the mechanisms that can explain the positive therapeutic effects of IVIg therapy. Consequently, selecting patients with abnormal Th17/Treg cell ratios could increase the success of IVIg therapy.