Hoping to get more insight into a role of vascular endothelial growth factor (VEGF), a putative substance involved in the development of preeclampsia, we measured concentrations of soluble VEGF receptor-1 (sVEGFR-1), a natural antagonist of VEGF, in serum from women with (n = 31) and without (n = 52) preeclampsia. The concentrations of sVEGFR-1 in serum from women with preeclampsia (median 7791 pg/mL) were > 6-fold higher than those from control (1132 pg/mL, p < 0.0001). The levels of sVEGFR-1 decreased markedly after delivery in both groups. Serum sVEGFR-1 levels of non-preeclamptic women were positively correlated with gestational age (r = 0.570, p < 0.0001), whereas those of preeclamptic women exhibited no correlation with gestational age (r= −0.130, p = 0.476). These findings may point to an involvement of sVEGFR-1 in the pathophysiology of preeclampsia possibly by antagonizing of VEGF effects on the formation of placental vasculature and maternal endothelial cell function.

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.

Significance: Men without spermatozoa or elongating spermatids in their testes have been considered sterile and are advised to consider using a sperm donor. However, these men may have round spermatids. We have been able to accurately identify these cells based on their structural and physical characteristics (verified by karyotyping and FISH). Round spermatid injection was effectively used in our clinic and resulted in the birth of 14 healthy babies. Although the current success rate of round spermatid injection is not very high compared with intracytoplasmic sperm injection, this procedure can be the last resort for men who cannot produce spermatozoa but wish to use their own genetic material to produce offspring.

The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express type 1 integral membrane protein Sushi domain containing 2 (SUSD2) but the role of these cells in the decidual transformation of this tissue in pregnancy is unknown. We used an antibody directed against SUSD2 (W5C5) to isolate perivascular (W5C5+) and nonperivascular (W5C5−) fibroblasts from mid-luteal biopsies. We show that SUSD2 expression, and hence the ratio of W5C5+:W5C5− cells, changes in culture depending on cell-cell contact and activation of the Notch signaling pathway. RNA sequencing revealed that cultures derived from W5C5+ progenitor cells remain phenotypically distinct by the enrichment of novel and established endometrial perivascular signature genes. In an undifferentiated state, W5C5+-derived cells produced lower levels of various chemokines and inflammatory modulators when compared with their W5C5− counterparts. This divergence in secretomes was switched and became more pronounced upon decidualization, which transformed perivascular W5C5+ cells into the dominant source of a range of chemokines and cytokines, including leukemia inhibitory factor and chemokine (C-C motif) ligand 7. Our findings suggest that the decidual response is spatially organized at the embryo-maternal interface with differentiating perivascular cells establishing distinct cytokine and chemokine profiles that could potentially direct trophoblast toward maternal vessels and govern local immune responses in pregnancy.

The forkhead transcription factor FOXO1, a downstream target of phosphatidylinositol-3-kinase/Akt signalling pathway, regulates cyclic differentiation and apoptosis in normal endometrium, but its role in endometrial carcinogenesis is unknown. Screening of endometrial cancer cell lines demonstrated that FOXO1 is expressed in HEC-1B cells, but not in Ishikawa cells, which in turn highly express the FOXO1 targeting E3-ubiquitin ligase Skp2. FOXO1 transcript levels were also lower in Ishikawa cells and treatment with the proteasomal inhibitor was insufficient to restore expression. Lack of FOXO1 expression in Ishikawa cells was not accounted for by differential promoter methylation or activity, but correlated with increased messenger RNA (mRNA) turnover. Comparative analysis demonstrated that HEC-1B cells proliferate slower, but are more resistant to paclitaxel-mediated cell death than Ishikawa cells, which were partially reversed upon silencing of FOXO1 in HEC-1B cells or its re-expression in Ishikawa cells. We further show that FOXO1 is required for the expression of the growth arrest- and DNA-damage-inducible gene GADD45α. Analysis of biopsy samples demonstrated a marked loss of FOXO1 and GADD45α mRNA and protein expression in endometrioid endometrial cancer compared to normal endometrium. Together, these observations suggest that loss of FOXO1 perturbs endometrial homeostasis, promotes uncontrolled cell proliferation and increases susceptibility to genotoxic insults.