PGF2α induces a pro-labour phenotypical switch in human myometrial cells that can be inhibited with PGF2α receptor antagonists.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1049440 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27117500.fastq.gz | Fastqsanger.gz | |||
| SRR27117501.fastq.gz | Fastqsanger.gz | |||
| SRR27117502.fastq.gz | Fastqsanger.gz | |||
| SRR27117503.fastq.gz | Fastqsanger.gz | |||
| SRR27117504.fastq.gz | Fastqsanger.gz |
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Project description:Preterm birth is the leading cause of infant morbidity and mortality. There has been interest in developing prostaglandin F2α (PGF2α) antagonists as a new treatment for preterm birth although much of the rationale for their use is based on studies in rodents where PGF2α initiates labour by regressing the corpus luteum and reducing systemic progesterone concentrations. How PGF2α antagonism would act in humans that do not have a fall in systemic progesterone remains unclear. One possibility, in addition to an acute stimulation of contractions, is a direct alteration of the myometrial smooth muscle cell state towards a pro-labour phenotype. In this study we developed an immortalised myometrial cell line, MYLA, derived from myometrial tissue obtained from a pregnant, non‐labouring patient as well as a novel class of PGF2α receptor (FP) antagonist. We verified the functionality of the cell line by stimulation with PGF2α, which resulted in Gαq specific coupling and Ca2+ release that were inhibited by FP antagonism. Compared to four published FP receptor antagonists, the novel FP antagonist N582707 was the most potent compound (Fmax 7.67 ± 0.63 (IC50 21.26 nM), AUC 7.30 ± 0.32 (IC50 50.43 nM) and frequency of Ca2+ oscillations 7.66 ± 0.41 (IC50 22.15 nM)). RNA‐sequencing of the MYLA cell line at 1, 3, 6, 12, 24 & 48 hours post PGF2α treatment revealed a transforming phenotype from a fibroblastic to smooth muscle mRNA profile. PGF2α treatment increased expression of MYLK, CALD1 and CNN1 as well as the pro-labour genes OXTR, IL6 and IL11 which were inhibited by FP antagonism. Concomitant with inhibition of a smooth muscle, pro-labour transition, FP antagonism increased the expression of the fibroblast marker genes DCN, FBLN1 and PDGFRA. Our findings suggest that in addition to the well described acute contractile effect, PGF2α transforms myometrial smooth muscle cells from a myofibroblast to smooth muscle, pro-labour like state, and that the novel compound N582707 has potential for prophylactic use in preterm labour management beyond its use as an acute tocolytic drug.
2023-12-13 | GSE249529 | GEO
Project description:This study identifies a transciptomic myometrial profile associated with dystocia in spontanous nulliparous term labour We used microarrays to compare myometrial biopsies obtained at cesarean section from women in spontaneous term labour
2011-09-17 | GSE32178 | GEO
Project description:This study identifies a transciptomic myometrial profile associated with dystocia in spontanous nulliparous term labour We used microarrays to compare myometrial biopsies obtained at cesarean section from women in spontaneous term labour Women in spontaneous labour undergoing cesarean section for dystocia (slow progressing labour) compared to women who had progressed in the second stage
2011-09-16 | E-GEOD-32178 | biostudies-arrayexpress
Project description:Circulating progesterone (P4) levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is functional withdrawal of P4 action at the myometrial level prior to labor onset. Mifepristone is widely used to induce human labour In this study, we aimed to establish and validate a model of human myometrial explants for the study of P4 action. Myometrial biopsies obtained at Caesearean section at term were dissected into explants after a portion was immediately snap-frozen (t=0). Transcriptomic comparison of paired explants and primary myometrial cells as well as the hTert immortalized myometrial cell line demonstrated that explants more closely resemble t=0.
2016-05-30 | GSE77830 | GEO
Project description:During pregnancy, the myometrium remains quiescent but at term, switches to a state capable of producing a series of coordinated contractions for the delivery of the fetus. Myometrial contractions of labour signify the normal physiological end-point of pregnancy but the biochemical onset of labour may occur at or before term via a series of changes in expression of labour associated genes that are responsible for controlling the activity of the uterus during pregnancy and parturition. There is increasing evidence that components of the cAMP-signalling pathway are up-regulated in the human myometrium during pregnancy to promote the relaxation of the myometrium until term. Our aim was to determine which cAMP-associated genes are important during pregnancy and parturition by exposing myometrial cells to forskolin and performing an a gene array. We then plan to study the trend of the cAMP-associated genes at different stages of gestation and during labour. In this study, we used microarrays to elucidate forskolin responsive genes in human myometrium. These data may provide a broader view of gene networks and cellular functions regulated by forskolin in human myometrial cells. In our future study, this will also help us understand the role of cAMP in human parturition. Primary cultures of human myometrial cells were grown from myometrial biopsies obtained at the time of elective caesarean section at term. Cells were exposed to forskolin (100 µM) for 48 hours, and then total RNA were extracted from each culture. Two comparisons were carried out including: 1. Control 2. Forksolin
2016-07-01 | E-GEOD-75799 | biostudies-arrayexpress
Project description:During pregnancy, the myometrium remains quiescent but at term, switches to a state capable of producing a series of coordinated contractions for the delivery of the fetus. Myometrial contractions of labour signify the normal physiological end-point of pregnancy but the biochemical onset of labour may occur at or before term via a series of changes in expression of labour associated genes that are responsible for controlling the activity of the uterus during pregnancy and parturition. There is increasing evidence that components of the cAMP-signalling pathway are up-regulated in the human myometrium during pregnancy to promote the relaxation of the myometrium until term. Our aim was to determine which cAMP-associated genes are important during pregnancy and parturition by exposing myometrial cells to forskolin and performing an a gene array. We then plan to study the trend of the cAMP-associated genes at different stages of gestation and during labour. In this study, we used microarrays to elucidate forskolin responsive genes in human myometrium. These data may provide a broader view of gene networks and cellular functions regulated by forskolin in human myometrial cells. In our future study, this will also help us understand the role of cAMP in human parturition.
2016-07-01 | GSE75799 | GEO
Project description:Circulating progesterone (P4) levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is functional withdrawal of P4 action at the myometrial level prior to labor onset. Mifepristone is widely used to induce human labour In this study, we aimed to establish and validate a model of human myometrial explants for the study of P4 action. Myometrial biopsies obtained at Caesearean section at term were dissected into explants after a portion was immediately snap-frozen (t=0). Transcriptomic comparison of paired explants and primary myometrial cells as well as the hTert immortalized myometrial cell line demonstrated that explants more closely resemble t=0. Biopsies obtained from non-laboring women at elective Caesarean section at term were divided into 3: (i) dissected and immediately snap-frozen (t=0), (ii) dissected into 3x3x3mm3myometrial explants and (iii) processed for primary cell culture. Explants, primary cells at passage 4 (the typical passage our group uses for experiments) and hTERT cells were cultured for a period of 30 hours without treatment. Total RNA was extracted and microarray analysis performed. 6 replicates were used for this study.
2016-05-30 | E-GEOD-77830 | biostudies-arrayexpress
Project description:Purpose: To chart the human myometrial transcriptomes before and after the onset of labour. Methods: Tophat splice junction mapping of paired-end reads, HTSeq to generate counts, cufflinks to track transcripts, DESeq, edgeR and baySeq to detect differentially expressed genes and principal component analysis for clustering analyses. Results: We mapped on average 14 million paired-end reads per sample (counting each end individually) to the human genome (build hg19) and covered the expressed transcriptome about 13 times with a TopHat-HTSeq workflow. We performed a comparative analysis with an analogous microarray study (Mittal et al., 2010) and found some overlap between the RNA-seq and the microarray data. Conclusions: Our study is the first RNA-seq study of the human myometrium before and after the onset of labour. We show that while microarray and RNA-seq studies may complement each other, RNA-seq has a much greater resolution. At term with and at term without labour human myometrial mRNA profiles were generated by deep sequencing, using Illumina GAIIx (five biological replicates each).
2014-02-17 | E-GEOD-50599 | biostudies-arrayexpress
Project description:Purpose: To chart the human myometrial transcriptomes before and after the onset of labour. Methods: Tophat splice junction mapping of paired-end reads, HTSeq to generate counts, cufflinks to track transcripts, DESeq, edgeR and baySeq to detect differentially expressed genes and principal component analysis for clustering analyses. Results: We mapped on average 14 million paired-end reads per sample (counting each end individually) to the human genome (build hg19) and covered the expressed transcriptome about 13 times with a TopHat-HTSeq workflow. We performed a comparative analysis with an analogous microarray study (Mittal et al., 2010) and found some overlap between the RNA-seq and the microarray data. Conclusions: Our study is the first RNA-seq study of the human myometrium before and after the onset of labour. We show that while microarray and RNA-seq studies may complement each other, RNA-seq has a much greater resolution.
2014-02-17 | GSE50599 | GEO