Dataset Information

Fetal and trophoblast PI3K p110? have distinct roles in regulating resource supply to the growing fetus in mice.

ABSTRACT: Studies suggest that placental nutrient supply adapts according to fetal demands. However, signaling events underlying placental adaptations remain unknown. Here we demonstrate that phosphoinositide 3-kinase p110? in the fetus and the trophoblast interplay to regulate placental nutrient supply and fetal growth. Complete loss of fetal p110? caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110? resulted in viable fetuses, abnormal placental development and a failure of the placenta to transport sufficient nutrients to match fetal demands for growth. Using RNA-seq we identified genes downstream of p110? in the trophoblast that are important in adapting placental phenotype. Using CRISPR/Cas9 we showed loss of p110? differentially affects gene expression in trophoblast and embryonic stem cells. Our findings reveal important, but distinct roles for p110? in the different compartments of the conceptus, which control fetal resource acquisition and growth.

SUBMITTER: Lopez-Tello J

PROVIDER: S-EPMC6634971 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus in mice.

López-Tello Jorge J Pérez-García Vicente V Khaira Jaspreet J Kusinski Laura C LC Cooper Wendy N WN Andreani Adam A Grant Imogen I Fernández de Liger Edurne E Lam Brian Yh BY Hemberger Myriam M Sandovici Ionel I Constancia Miguel M Sferruzzi-Perri Amanda N AN

eLife 20190626

Studies suggest that placental nutrient supply adapts according to fetal demands. However, signaling events underlying placental adaptations remain unknown. Here we demonstrate that phosphoinositide 3-kinase p110α in the fetus and the trophoblast interplay to regulate placental nutrient supply and fetal growth. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophob ...[more]

PMID: 31241463

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Project description:ContextDysregulated immune hemostasis occurs in unexplained recurrent spontaneous abortion (URSA). Synthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), hydrogen sulfide (H2S) promotes regulatory T-cell differentiation and regulates immune hemostasis; yet, its role in URSA is elusive.ObjectiveTo determine if H2S plays a role in early pregnancy and if dysregulated H2S signaling results in recurrent spontaneous abortion.DesignFirst trimester placenta villi and decidua were collected from normal and URSA pregnancies. Protein expression was examined by immunohistochemistry and immunoblotting. Human trophoblast HTR8/SVneo and JEG3 cells were treated with H2S donors; HTR8/SVneo cells were transfected with CBS ribonucleic acid interference (RNAi) or complementary deoxyribonucleic acid. Cell migration and invasion were determined by transwell assays; trophoblast transcriptomes were determined by RNA sequencing (RNA-seq). Wild-type, CBS-deficient, and CBA/J × DBA/2 mice were treated with CBS and CSE inhibitors or H2S donors to determine the role of H2S in early pregnancy in vivo.ResultsCBS and CSE proteins showed cell-specific expressions, but only CBS decreased in the villous cytotrophoblast in URSA versus normal participants. H2S donors promoted migration and invasion and MMP-2 and VEGF expression in human placenta trophoblast cells that contain SV40 viral deoxyribonucleic acid sequences (HTR8/SVneo) and human placenta trophoblast cells (JEG3 cells), similar to forced CBS expression in HTR8/SVneo cells. The CBS-responsive transcriptomes in HTR8/SVneo cells contained differentially regulated genes (ie, interleukin-1 receptor and prostaglandin-endoperoxide synthase 2) that are associated with nuclear factor-κB-mediated inflammatory response. In vivo, dysregulated CBS/H2S signaling significantly increased embryonic resorption and decidual T-helper 1/T-helper 2 imbalance in mice, which was partially rescued by H2S donors.ConclusionCBS/H2S signaling maintains early pregnancy, possibly via regulating maternal-fetal interface immune hemostasis, offering opportunities for H2S-based immunotherapies for URSA.

Dataset Information

Fetal and trophoblast PI3K p110? have distinct roles in regulating resource supply to the growing fetus in mice.

Publications

Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus in mice.

Similar Datasets

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