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The biologically significant phenomenon that the fetus can survive immune attacks from the mother has been demonstrated in mammals. The survival mechanism depends on the fetus and placenta actively defending themselves against attacks by maternal T cells, achieved through the localized depletion of the amino acid L-tryptophan by an enzyme called indoleamine 2,3-dioxygenase. These findings were entirely unexpected and pose important questions regarding diseases related to human pregnancy and their prevention during human pregnancy. Specifically, the role of this mechanism, as discovered in mice, in humans remains unknown, as does the extent to which impaired activation of this process contributes to major clinical diseases in humans. We have, thus, elucidated several key aspects of this enzyme expressed in the human placenta both in normal and abnormal human pregnancy. The questions addressed in this brief review are as follows: (1) localization and characteristics of human placental indoleamine 2,3-dioxygenas; (2) overall tryptophan catabolism in human pregnancy and a comparison of indoleamine 2,3-dioxygenase expression levels between normal and pre-eclamptic pregnancy; (3) controlling trophoblast invasion by indoleamine 2,3-dioxygenase and its relation to the pathogenesis of placenta accrete spectrum.

While common in viral infections and neoplasia, spontaneous cell-cell fusion, or syncytialization, is quite restricted in healthy tissues. Such fusion is essential to human placental development, where interactions between trophoblast-specific human endogenous retroviral (HERV) envelope proteins, called syncytins, and their widely-distributed cell surface receptors are centrally involved. We have identified the first host cell-encoded protein that inhibits cell fusion in mammals. Like the syncytins, this protein, called suppressyn, is HERV-derived, placenta-specific and well-conserved over simian evolution. In vitro, suppressyn binds to the syn1 receptor and inhibits syn1-, but not syn2-mediated trophoblast syncytialization. Suppressyn knock-down promotes cell-cell fusion in trophoblast cells and cell-associated and secreted suppressyn binds to the syn1 receptor, ASCT2. Identification of the first host cell-encoded inhibitor of mammalian cell fusion may encourage improved understanding of cell fusion mechanisms, of placental morphogenesis and of diseases resulting from abnormal cell fusion.

Up to 8% of the human genome is of retroviral origin. These stably integrated retroviral sequences that characterize the human endogenous retrovirus (HERV) arose from retroviral infections that occurred more than 25 million years ago. The host and the retrovirus have subsequently coevolved as retrovirally derived genetic material is propagated in a Mendelian fashion. Although most HERV sequences are silenced, several have been described that are functional. The effects of some HERV-derived products are linked to human disease; others appear essential to human organ function. The human placenta, unique in its active expression of retroviral sequences that are not expressed in other tissues, may hold the key to an improved understanding of the functional significance of HERVs. In this review, we discuss the contribution of retroelements, particularly HERVs, to placental function and dysfunction. We describe fusogenic and immunosuppressive HERV activities and emphasize epigenetic regulation of retroelement expression.

The goal of the present study was to investigate inter-individual and age-dependent variation of global DNA methylation in human tissues. In this work, we examined 5-methyldeoxycytidine ((met)C) content by HPLC in human peripheral blood leukocytes obtained from 76 healthy individuals of ages varying from 4 to 94 years (yr), and 39 human placentas from various gestational stages. The HPLC analysis revealed a significant variation of (met)C across individuals and is consistent with the previous findings of age-dependent decrease of global methylation levels in human tissues. The age-dependent decrease of (met)C was relatively small, but statistically highly significant (p= 0.0002) in the aged group (65.9 +/- 8.9 [mean age +/- SD] yr; n = 22) in comparison to the young adult group (19.3 +/- 1.4 yr; n = 21). Males showed a subtle but statistically significant higher mean (met)C content than females. In contrast to the peripheral blood samples, DNA extracted from placentas exhibited gestational stage-dependent increase of methylation levels that appeared to inversely correlate with the expression levels of human endogenous retroviruses. These data may be helpful in further studies of DNA methylation, such as inheritance of epigenetic patterns, environment-induced changes, and involvement of epigenetic changes in disease.