Project description:The pregnant decidua is infiltrated by many immune cells which are thought to originate in the bone marrow (BM) promoting pregnancy. CXCR4 is a key regulator of the development of NK cells and dendritic cells, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. To generate tamoxifen-inducible CXCR4 knockout mice, we used the Cre/LoxP tamoxifen-inducible system. For animal experiments, Cre+/CXCR4fl/fl mice and their Cre-/CXCR4fl/fl littermates were used. After tamoxifen treatment, we refer to Cre-/CXCR4fl/wt mice as WT (wild type), and Cre+/CXCR4fl/null mice as CXCR4 KO (knockout). For adoptive bone marrow transplant (BMT) experiments, BMT was performed from either WT GFP transgenic male donor mice into WT or CXCR4 KO females, or from CXCR4 KO male donors into CXCR4 KO females as negative control. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development and pregnancy maintenance.
Project description:CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increased granulocytes in the decidua, along with increased leukocyte numbers in peripheral blood. We found that CXCR4-deficient mice had abnormal decidual NK cell aggregates and NK cell infiltration into trophoblast areas beyond the giant cell layer. This was associated with low NK cell expression of granzyme B, a NK cell granule effector, indicative of NK cell dysfunction. Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes. Importantly, adoptive BM transfer of WT CXCR4+ BM cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development, and pregnancy maintenance.
Project description:The placenta is a potent endocrine organ that secretes hormones with metabolic effects into maternal circulation. On the other hand, the liver, which is the main detoxification organ of the body, plays a key role in regulating maternal glucose and insulin metabolism during pregnancy. Failures in the production of placental hormones and/or the liver to adapt its structure and function to pregnancy can result in metabolic diseases such as gestational diabetes. Previous work has shown that the imprinted Igf2-H19 locus is involved in controlling placental endocrine function in mice. This study used conditional mis-expression of the Igf2-H19 locus to induce placental endocrine malfunction and study its consequences on hepatic gene regulation during pregnancy.
Project description:In a previous study, 50% calorie restriction in mice from days 1.5-11.5 of pregnancy resulted in reduced placental weights and areas, relatively sparing of labyrinth zone area compared to junctional zone area, and dramatic changes in global gene expression profiles. Here we examined placental gene expression at day 18.5, after the return to normal feeding to see whether differences were reversible Mice were randomized to 2 treatment groups on day 1.5 of pregnancy: (1) ad libitum fed (control) (2) 50% food restriction (restricted). Mice were returned to ad libitum feed on d11.5, sacrificed on d18.5 and placentas were collected.
Project description:We hypothesized that the trophoblast secretes anti-angiogenic factors, which increase in late pregnancy to limit angiogenesis. Therefore, we determined the paracrine effect of primary human trophoblasts from early versus late pregnancy on the angiogenic potential of isolated feto-placental endothelial cells. We found that the expression and secretion of anti-angiogenic factors differs in early vs late pregnancy, and differentially affects feto-placental angiogenesis.
Project description:Maternal obesity is becoming a major health consideration for successful pregnancy outcomes. There is growing proof that maternal obesity has a negative influence on placental development and function, thereby adversely influencing offspring programming and health outcomes. However, the molecular mechanisms underlying these processes are so far poorly understood. We set out to analyse term placenta whole transcriptome in obese (n=5) and normoweight women (n=5), using Affymetrix microarray platform compromising of 50,000 probe sets. Our analysis shows that the placental transcriptome differs between normoweight and obese women. Different processes and pathways among placenta from obese women were dysregulated, including inflammation and immune responses, lipid metabolism, cell death and survival and cancer pathways, vasculogenesis and angiogenesis, and glucocorticoid receptor signaling pathway. Together, this global gene expression profiling approach demonstrates and confirms that maternal obesity creates a unique in utero environment that impairs placental transcriptome.
Project description:We report that the effect of GDM on gene expression differs between feto-placental endothelial cells of male vs female progeny, i.e. after pregnancy with a male or female offspring.
Project description:Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relationships between maternal 25(OH)D concentrations and fetal physiology. Here, we demonstrate active placental uptake of 25(OH)D3 by endocytosis and placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the fetal and maternal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than solely the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer, including transcriptional activation and inflammatory responses. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta; with widespread effects on the placenta itself. These data show complex and synergistic interplay between vitamin D and the placenta, and inform possible interventions to optimise placental function to better support fetal growth and the maternal adaptations to pregnancy.
Project description:Elevated testosterone levels increase maternal blood pressure and decrease uterine blood flow in pregnancy, resulting in abnormal perinatal outcomes. The placenta is the key in understanding the pathophysiological processes associated with pregnancy. The current study is designed to characterize the genes essential for placental function to understand the mechanisms underlying normal and pathological gestation.