Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia.

INTRODUCTION: The dysregulation of maternal-fetal immune tolerance is one of the proposed mechanisms leading to preeclampsia. Galectins are key regulator proteins of the immune response in vertebrates and maternal-fetal immune tolerance in eutherian mammals. Previously we found that three genes in a Chr19 cluster encoding for human placental galectin-13 (PP13), galectin-14 and galectin-16 emerged during primate evolution and may confer immune tolerance to the semi-allogeneic fetus. MATERIALS AND METHODS: This study involved various methodologies for gene and protein expression profiling, genomic DNA methylation analyses, functional assays on differentiating trophoblasts including gene silencing, luciferase reporter and methylation assays. These methods were applied on placental specimens, umbilical cord blood cells, primary trophoblasts and BeWo cells. Genomic DNA sequences were analyzed for transposable elements, transcription factor binding sites and evolutionary conservation. RESULTS AND DISCUSSION: The villous trophoblastic expression of Chr19 cluster galectin genes is developmentally regulated by DNA methylation and induced by key transcription factors of villous placental development during trophoblast fusion and differentiation. This latter mechanism arose via the co-option of binding sites for these transcription factors through promoter evolution and the insertion of an anthropoid-specific L1PREC2 transposable element into the 5' untranslated region of an ancestral gene followed by gene duplication events. Among placental Chr19 cluster galectin genes, the expression of LGALS13 and LGALS14 is down-regulated in preterm severe preeclampsia associated with SGA. We reveal that this phenomenon is partly originated from the dysregulated expression of key transcription factors controlling trophoblastic functions and galectin gene expression. In addition, the differential DNA methylation of these genes was also observed in preterm preeclampsia irrespective of SGA. CONCLUSIONS: These findings reveal the evolutionary origins of the placental expression of Chr19 cluster galectins. The complex dysregulation of these genes in preeclampsia may alter immune tolerance mechanisms at the maternal-fetal interface.

"Trophoblast islands of the chorionic connective tissue" (TICCT): a novel placental histologic feature.

INTRODUCTION: We found isolated or clustered trophoblasts in the chorionic connective tissue of the extraplacental membranes, and defined this novel histologic feature as the "trophoblast islands of the chorionic connective tissue" (TICCT). This study was conducted to determine the clinical significance of TICCT. METHODS: Immunohistochemistry for cytokeratin-7 was performed on the chorioamniotic membranes (N = 2155) obtained from singleton pregnancies of 1199 uncomplicated term and 956 preterm deliveries. The study groups comprised 1236 African-American and 919 Hispanic women. Gestational age ranged from 24(+0) weeks to 41(+6) weeks. Multiple logistic regression analysis was performed to investigate the magnitude of association between patient characteristics and the presence of TICCT. RESULTS: The likelihood of TICCT was significantly associated with advancing gestational age both in term (OR: 1.29, 95% CI: 1.16-1.45, p < 0.001) and preterm deliveries (OR: 1.19, 95% CI: 1.07-1.32, p = 0.001) . Hispanic women were less likely than African-American women to have TICCT across gestation in term (OR: 0.23, 95% CI: 0.18-0.31, p < 0.001) and preterm pregnancies (OR: 0.41, 95% CI: 0.29-0.58, p < 0.001). Women with a female fetus were significantly more likely to have TICCT than women with a male fetus, in both term (OR: 1.64, 95% CI: 1.28-2.11, p < 0.001) and preterm gestations (OR: 2.04, 95% CI: 1.46-2.85, p < 0.001). TICCT was 40% less frequent in the presence of chronic placental inflammation [term (OR: 0.60, 95% CI: 0.45-0.81, p = 0.001) and preterm gestations (OR: 0.58, 95% CI: 0.40-0.84, p = 0.003)] and in parous women at term (OR: 0.60, 95% CI: 0.44-0.81, p = 0.001). CONCLUSIONS: Our findings suggest that the duration of pregnancy, fetal sex, and parity may influence the behavior of extravillous trophoblast and placental mesenchymal cells.