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Computational flow cytometry analysis reveals a unique immune signature of the human maternal-fetal interface.

ABSTRACT: PROBLEM:Decidual immune dysregulation is thought to underlie major pregnancy disorders; however, incomplete understanding of the decidual immune interface has hampered the mechanistic investigation. METHOD OF STUDY:Human term decidua was collected, and single-cell phenotypic information was acquired by highly polychromatic flow cytometry. Cellular identity analysis was performed with t-distributed stochastic neighbor embedding, DensVM clustering, and matched to CellOntology database. RESULTS:Traditional analytical methods validated known cellular T and dendritic cell subsets in human term decidua. Computational analysis revealed a complex and tissue-specific decidual immune signature in both the innate and adaptive immune compartments. CONCLUSION:Polychromatic flow cytometry with a streamlined computational analysis pipeline is a feasible approach to comprehensive immunome mapping of human term decidua. As an unbiased, standardized method of investigation, computational flow cytometry promises to unravel the immune pathology of pregnancy disorders.

SUBMITTER: Vazquez J

PROVIDER: S-EPMC5725254 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Computational flow cytometry analysis reveals a unique immune signature of the human maternal-fetal interface.

Vazquez Jessica J Chavarria Melina M Li Yan Y Lopez Gladys E GE Stanic Aleksandar K AK

American journal of reproductive immunology (New York, N.Y. : 1989) 20171014 1

<h4>Problem</h4>Decidual immune dysregulation is thought to underlie major pregnancy disorders; however, incomplete understanding of the decidual immune interface has hampered the mechanistic investigation.<h4>Method of study</h4>Human term decidua was collected, and single-cell phenotypic information was acquired by highly polychromatic flow cytometry. Cellular identity analysis was performed with t-distributed stochastic neighbor embedding, DensVM clustering, and matched to CellOntology databa ...[more]

PMID: 29030900

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Project description:BackgroundPreeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the maternal-fetal interface (MFI) may be associated with preeclampsia onset. Recent studies have revealed the reduced expression pattern of HLA-F at the MFI in preeclampsia, while the mechanism of it mediating maternal fetal immune tolerance has not been revealed.MethodsSingle-cell RNA sequencing on placental decidua was performed to reveal the immune disturbances landscape at the MFI in preeclampsia. Human Jar cells and NK-92MI cells were employed to study the role of HLA-F in trophoblasts and lymphocyte.ResultsA total of 101,250 cells were classified into 22 cell clusters. Disease-related IGFBP1+SPP1+ extracellular villus trophoblast (EVT) was identified in the preeclamptic placental decidua, accompanied by newly discovered immune cellular dysfunction such as reduced ribosomal functions of NK populations and abnormal expression of antigen-presenting molecules in most cell clusters. Certain genes that are characteristic of the intermediate stage of myeloid or EVT cell differentiation were found to have unexplored but important functions in the pathogenesis of preeclampsia; specifically, we detected enhanced cell cross-talk between IGFBP1+SPP1+ EVT2 or SPP1+M1 cells and their receptor cell populations at the MFI of PE patients compared to controls. With respect to HLA-F, mIF staining confirmed its reduced expression in PE samples compared to controls. Over-expression of HLA-F in Jar cells promoted cell proliferation, invasion, and migration while under-expression had the opposite effect. In NK-92MI cells, over-expression of HLA-F increased the secretion of immunoregulation cytokines such as CSF1 and CCL22, and promoted adaptive NKG2C+NK cell transformation.ConclusionsWe revealed the immune disturbance landscape at the MFI in preeclampsia. Our findings regarding cellular heterogeneity and immune cellular dysfunction, as revealed by scRNA-seq, and the function of HLA-F in cells provide new perspectives for further investigation of their roles in the pathogenesis of preeclampsia, and then provide potential new therapeutic target.

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.

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Computational flow cytometry analysis reveals a unique immune signature of the human maternal-fetal interface.

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Computational flow cytometry analysis reveals a unique immune signature of the human maternal-fetal interface.

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