Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term (original) (raw)
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Choriodecidua and amnion exhibit selective leukocyte chemotaxis during term human labor
American Journal of Obstetrics and Gynecology, 2011
The purpose of this study was to compare the chemotactic activity of the choriodecidua and amnion, and to identify the phenotype of the leukocytes chemoattracted by each tissue. STUDY DESIGN: Amnion, choriodecidua and whole fetal membranes extracts were obtained from women at term (Ͼ37 weeks of gestation) with or without labor (n ϭ 5 each). Extracts were assayed for leukocyte chemotactic activity, and the number and phenotype of the chemoattracted leukocytes were characterized by flow cytometry. RESULTS: Although all of the extracts exhibited chemotactic activity, more leukocytes were chemoattracted by the choriodecidua and the whole fetal membranes during labor compared with no labor (P ϭ .010, .008). During labor the choriodecidua is responsible for granulocyte, Tlymphocyte, monocyte, and natural killer-cell chemoattraction, and the amnion is responsible for B-lymphocyte chemoattraction. CONCLUSION: Choriodecidua and amnion exhibit chemotactic activity for selective leukocytes and thus, each fetal membrane differentially regulates leukocyte chemotactic activity during labor.
Journal of Reproductive Immunology, 2010
Rupture of the fetal membranes during human labor is associated with an inflammatory process localized to the maternal-fetal interface. There is evidence that specific leukocytes subsets are attracted to the choriodecidua, and that after homing they condition a local inflammatory microenvironment, possibly being directly involved in rupture of the membranes. In this study our aim was to compare the phenotypes and function of leukocytes located in the placental intervillous blood with peripheral leukocytes obtained before or after labor, including expression of modulators of inflammation in these cells. Flow cytometry revealed that the proportion of CD14 + cells is increased in intervillous blood, suggesting the participation of monocytes/macrophages during labor. Real time qRT-PCR showed that at term gestation and particularly during labor, placental blood leukocytes adopt a different expression pattern of pro-inflammatory cytokines than leukocytes in peripheral blood, including IL-1 and IL-1RA. During labor, both placental and peripheral leukocytes increase their secretion of matrix metalloproteinase-9. Moreover, we showed that placental leukocytes respond differently than peripheral leukocytes to bacterial lipopolysaccharide, secreting differential amounts of TNF-␣, IL-1 and IL-6. Finally, a preliminary proteomic characterization of placental leukocytes revealed a significantly higher number of individual proteins than in peripheral leukocytes. Our results support the existence of selective subsets of leukocytes recruited to the maternal-fetal interface that may participate in the triggering of parturition.
American Journal of Obstetrics and Gynecology
, on behalf of the Global Alliance to Prevent Prematurity and Stillbirth Systems Biology of Preterm Birth Team BACKGROUND: Preterm birth is the leading cause of newborn death worldwide, and is associated with significant cognitive and physiological challenges in later life. There is a pressing need to define the mechanisms that initiate spontaneous preterm labor, and for development of novel clinical biomarkers to identify high-risk pregnancies. Most preterm birth studies utilize fetal tissues, and there is limited understanding of the transcriptional changes that occur in mothers undergoing spontaneous preterm labor. Earlier work revealed that a specific population of maternal peripheral leukocytes (macrophages/monocytes) play an active role in the initiation of labor. Thus, we hypothesized that there are dynamic gene expression changes in maternal blood leukocytes during preterm labor. OBJECTIVE: Using next-generation sequencing we aim to characterize the transcriptome in whole blood leukocytes and peripheral monocytes of women undergoing spontaneous preterm labor compared to healthy pregnant women who subsequently delivered at full term. STUDY DESIGN: RNA sequencing was performed in both whole blood and peripheral monocytes from women who underwent preterm labor (24-34 weeks of gestation, N ¼ 20) matched for gestational age to healthy pregnant controls (N ¼ 30). All participants were a part of the Ontario Birth Study cohort (Toronto, Ontario, Canada). RESULTS: We identified significant differences in expression of 262 genes in peripheral monocytes and 184 genes in whole blood of women who were in active spontaneous preterm labor compared to pregnant women of the same gestational age not undergoing labor, with 43 of these genes differentially expressed in both whole blood and peripheral monocytes. ADAMTS2 expression was significantly increased in women actively undergoing spontaneous preterm labor, which we validated through digital droplet reverse transcriptase polymerase chain reaction. Intriguingly, we have also identified a number of gene sets including signaling by stem cell factor-KIT, nucleotide metabolism, and trans-Golgi network vesicle budding, which exhibited changes in relative gene expression that was predictive of preterm labor status in both maternal whole blood and peripheral monocytes. CONCLUSION: This study is the first to investigate changes in both whole blood leukocytes and peripheral monocytes of women actively undergoing spontaneous preterm labor through robust transcript measurements from RNA sequencing. Our unique study design overcame confounding based on gestational age by collecting blood samples from women matched by gestational age, allowing us to study transcriptomic changes directly related to the active preterm parturition. We performed RNA profiling using whole genome sequencing, which is highly sensitive and allowed us to identify subtle changes in specific genes. ADAMTS2 expression emerged as a marker of prematurity within peripheral blood leukocytes, an accessible tissue that plays a functional role in signaling during the onset of labor. We identified changes in relative gene expression in a number of gene sets related to signaling in monocytes and whole blood of women undergoing spontaneous preterm labor compared to controls. These genes and pathways may help identify potential targets for the development of novel drugs for preterm birth prevention.
Molecular Markers of Preterm Labor in the Choriodecidua
Reproductive Sciences, 2010
Since relevant biochemical changes are known to begin at the choriodecidual interface some weeks before actual clinical onset of labor, we hypothesized that the preterm choriodecidua may display gene and protein expression patterns specific to preterm labor. Transcriptomic (microarray) and proteomic (two-dimensional gel electrophoresis (2DGE)) profiling methodologies were utilized to compare changes in choriodecidual tissue collected from women who delivered before 35 weeks of gestation following spontaneous preterm labor (n=12) and gestation-matched non-laboring controls (n=7). Additionally, 2DGE was used to compare differences in protein expression during term and preterm labor and to construct a choriodecidual proteome map. Overall, expressed transcripts and proteins indicated active tissue remodelling independent of labor status and an association with inflammatory processes during labor. Spontaneous, infection-induced and abruption-associated
PeerJ, 2017
Background Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition. Methods Samples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment (n = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and wi...
Biology of Reproduction, 2021
The complex physiologic process of parturition includes the onset of labor, which requires the orchestrated stimulation of a common pathway involving uterine contractility, cervical ripening, and chorioamniotic membrane activation. However, the labor-specific processes taking place in these tissues have limited use as predictive biomarkers unless they can be probed in non-invasive samples, such as the peripheral blood. Herein, we utilized a transcriptomic dataset to assess labor-specific changes in the peripheral blood of women who delivered at term. We identified a set of genes that were differentially expressed with labor and enriched for immunological processes, and these gene expression changes were strongly correlated with results from prior studies, providing in silico validation of our findings. We then identified significant correlations between labor-specific transcriptomic changes in the maternal circulation and those detected in the chorioamniotic membranes, myometrium, and cervix of women at term, demonstrating that tissue-specific labor signatures are partly mirrored in the peripheral blood. Finally, we demonstrated a significant overlap between the peripheral blood transcriptomic changes in term parturition and those observed in asymptomatic women, prior to the diagnosis of preterm prelabor rupture of the membranes, who ultimately delivered preterm. Collectively, we provide evidence that the normal process of labor at term is characterized by a unique immunological expression signature, which may serve as a useful tool for assessing labor status and for potentially identifying women at risk for preterm birth.
Scientific Reports, 2019
Histological chorioamnionitis (HCA) is an infection of fetal membranes and complicates 5.2% to 28.5% of all live births. HCA is associated with increased mortality and morbidity in both premature and term neonates. exposure to HCA may have long-term consequences, including an increased risk for allergic disorders and asthma later in childhood, the mechanism(s) of which are still not yet well understood. the objective of this study was to determine the mRNA transcriptome of cord blood mononuclear leukocytes from term neonates to identify key genes and pathways involved in HCA. We found 366 differentially expressed probe IDs with exposure to HCA (198 upregulated, 168 downregulated). These transcriptomes included novel genes and pathways associated with exposure to HCA. The differential gene expression included key genes regulating inflammatory, immune, respiratory and neurological pathways, which may contribute to disorders in those pathways in neonates exposed to HCA. our data may lead to understanding of the role of key genes and pathways identified on the long-term sequelae related to exposure to HCA, as well as to identifying potential markers and therapies to prevent HCAassociated complications. Chorioamnionitis (CA) is an infection of the fetal membranes and placenta that complicates 5.2% of all live births 1. The prevalence of histological CA (HCA) in term neonates with spontaneous labor is 23.6-28.7% 2,3. Approximately 500,000 to one million infants in the United States are born each year to mothers diagnosed with HCA. Exposure to HCA may have long-term consequences, including an increased risk for allergic disorders and asthma later in childhood 4-6. Additionally, studies have demonstrated that exposure to HCA can also lead to developmental delay and cerebral palsy in preterm and term infants 7-9. Asthma and other allergic chronic diseases during childhood affect greater than 7 million children in the United States 10. Although HCA is associated with the development of asthma, allergic disorders, and neurodevelopmental impairment, the exact mechanism for these complications is unknown. Exposure to infection during late fetal life is likely to incite epigenetic changes, which may modulate the immune and neurological systems and increase the risk for development of neurological and allergic disorders later in life. Gene expression studies of cells and tissues have become a major tool for discovery in the pathogenesis of various diseases. Global gene expression by transcriptomic analysis can uncover gene signatures and help delineate molecular pathways involved in the development of asthma, allergy, and neurodevelopmental impairment in neonates born to mothers with HCA. Previous studies have reported differential gene expression patterns associated
Fetal membranes exhibit selective leukocyte chemotaxic activity during human labor
Journal of Reproductive Immunology, 2009
One of the characteristics of the labor process in women is leukocyte recruitment into reproductive tissues. These migrating cells may play a role in the induction of functional and biochemical changes associated with the rupture of fetal membranes during labor. This study was undertaken to assess whether human fetal membranes induce leukocyte chemotaxis during labor as well as to identify and characterize leukocyte chemoattractants secreted by these tissues. Leukocyte chemotactic activity of fetal membrane extracts obtained from women with full-term pregnancies and spontaneous active labor was compared with extracts from women without labor. The number and phenotype of attracted leukocytes were analyzed by flow cytometry. Chemokines were quantified using a Multiplex system and were identified by immunofluorescence histochemistry. Although all tested extracts induced chemotaxis of leukocytes, those prepared from women undergoing labor induced higher responses. Polymorphonuclear leukocyte chemotaxis increased approximately three-fold in response to extract from fetal membranes with labor. The same extracts elicited a significant increase in attracted monocytes (36-fold) as well as T and B lymphocytes, and NK cells (all five-fold) when compared to extracts from women without labor. This enhanced chemotactic activity was associated with the presence of IL-8, MCP-1, IP-10 and MIP-1␣. We conclude that fetal membrane extracts obtained from women during labor exhibit selective chemotaxis for specific leukocyte subpopulations in vitro. This process may contribute to a microenvironment composed of specific leukocytes that promotes and amplifies biochemical changes in the fetal membranes during labor.