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Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

ABSTRACT: BACKGROUND:Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS:Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS:We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS:Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies.

SUBMITTER: Migale R

PROVIDER: S-EPMC4904357 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

Migale Roberta R MacIntyre David A DA Cacciatore Stefano S Lee Yun S YS Hagberg Henrik H Herbert Bronwen R BR Johnson Mark R MR Peebles Donald D Waddington Simon N SN Bennett Phillip R PR

BMC medicine 20160613 1

<h4>Background</h4>Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human d ...[more]

PMID: 27291689

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Project description:BackgroundMost labor-related problems can be attributed to the uterine myometrium muscle, as this irritable tissue must suppress its irritability potential during pregnancy. Unfortunately, fewer studies have investigated the causes of this lack of suppression in preterm labor.MethodsWe conducted a scoping narrative review using three online databases (PubMed, Scopus, and Science Direct).ResultsThe review focused on ion channel functions in the myometrium, including sodium channels [Na K-ATPase, Na-activated K channels (Slo2), voltage-gated (SCN) Na+, Na+ leaky channels, nonselective (NALCN) channels], potassium channels [KATP (Kir6) channels, voltage-dependent K channels (Kv4, Kv7, and Kv11), twin-pore domain K channels (TASK, TREK), inward rectifier Kir7.1, Ca2+-activated K+ channels with large (KCNMA1, Slo1), small (KCNN1-3), intermediate (KCNN4) conductance], and calcium channels [L-Type and T-type Ca2+ channels, calcium-activated chloride channels (CaCC)], as well as hyperpolarization-activated cation channels. These channels' functions are associated with hormonal effects such as oxytocin, estrogen/progesterone, and local prostaglandins.ConclusionElectromechanical/hormonal activity and environmental autocrine factors can serve as the primary practical basis for premature uterine contractions in term/preterm labor. Our findings highlight the significance of.1.the amplitude rate of hyperpolarization and the frequency of contractions,2.changes in the estrogen/progesterone ratio,3.Prostaglandins E/F involvement in initiating potential spikes and the increase of intracytoplasmic Ca2+.This narrative study highlights the range of hyperpolarization and the frequency of myometrium contractions as crucial factors. The synchronized complex progress of estrogen to progesterone ratio and prostaglandins plays a significant role in initiating potential spikes and increasing intracytoplasmic Ca2+, which further influences the contraction process during labor. Insights into myometrium physiology gained from this study may pave the way for much-needed new treatments to reduce problems associated with normal and preterm labor.

Project description:During pregnancy, two fetomaternal interfaces, the placenta-decidua basalis and the fetal membrane-decidua parietals, allow for fetal growth and maturation and fetal-maternal crosstalk, and protect the fetus from infectious and inflammatory signaling that could lead to adverse pregnancy outcomes. While the placenta has been studied extensively, the fetal membranes have been understudied, even though they play critical roles in pregnancy maintenance and the initiation of term or preterm parturition. Fetal membrane dysfunction has been associated with spontaneous preterm birth (PTB, < 37 weeks gestation) and preterm prelabor rupture of the membranes (PPROM), which is a disease of the fetal membranes. However, it is unknown how the individual layers of the fetal membrane decidual interface (the amnion epithelium [AEC], the amnion mesenchyme [AMC], the chorion [CTC], and the decidua [DEC]) contribute to these pregnancy outcomes. In this study, we used a single-cell transcriptomics approach to unravel the transcriptomics network at spatial levels to discern the contributions of each layer of the fetal membranes and the adjoining maternal decidua during the following conditions: scheduled caesarian section (term not in labor [TNIL]; n = 4), vaginal term in labor (TIL; n = 3), preterm labor with and without rupture of membranes (PPROM; n = 3; and PTB; n = 3). The data included 18,815 genes from 13 patients (including TIL, PTB, PPROM, and TNIL) expressed across the four layers. After quality control, there were 11,921 genes and 44 samples. The data were processed by two pipelines: one by hierarchical clustering the combined cases and the other to evaluate heterogeneity within the cases. Our visual analytical approach revealed spatially recognized differentially expressed genes that aligned with four gene clusters. Cluster 1 genes were present predominantly in DECs and Cluster 3 centered around CTC genes in all labor phenotypes. Cluster 2 genes were predominantly found in AECs in PPROM and PTB, while Cluster 4 contained AMC and CTC genes identified in term labor cases. We identified the top 10 differentially expressed genes and their connected pathways (kinase activation, NF-κB, inflammation, cytoskeletal remodeling, and hormone regulation) per cluster in each tissue layer. An in-depth understanding of the involvement of each system and cell layer may help provide targeted and tailored interventions to reduce the risk of PTB.

Dataset Information

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

Publications

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

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