Transcriptional Dynamics of Cultured Human Villous Cytotrophoblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86171 | GEO | 2017/03/31
SECONDARY ACCESSION(S): PRJNA340445
REPOSITORIES: GEO
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Project description:During human pregnancy, cytotrophoblasts (CTBs) play key roles in uterine invasion, vascular remodeling, and anchoring of the feto-placental unit. Due to the challenges associated with studying human placentation in utero, cultured primary villous CTBs are used as a model of the differentiation pathway that leads to invasion of the uterine wall. In vitro, CTBs emulate in vivo cell behaviors, such as migration, aggregation, and substrate penetration. Although some of the molecular features related to these cell behaviors have been described, the underlying mechanisms, at a global level, remain undefined at midgestation. Thus, in this study, we characterized second-trimester CTB differentiation/invasion in vitro, correlating the major morphological transitions with the transcriptional changes that occurred at these steps. After plating on Matrigel as individual cells, CTBs migrated toward each other and formed multicellular aggregates. In parallel, using a microarray approach, we observed differentially expressed (DE) genes across time, which were enriched for numerous functions, including cell migration, vascular remodeling, morphogenesis, cell communication, and inflammatory signaling. DE genes encoded several molecules that we and others previously linked to critical CTB function in vivo, suggesting that the novel DE molecules we discovered played important roles. Immunolocalization confirmed that CTBs in situ gave a signal for two of the most highly expressed genes in vitro. In summary, we characterized, at a global level, the temporal dynamics of primary human CTB gene expression in culture. These data will enable future analyses of various types of in vitro perturbations-for example, modeling disease processes and environmental exposures.
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Project description:Uterine Natural Killer (uNK) cells regulate essential developmental processes at the maternal-fetal interface during early pregnancy. Uterine NK cell functions are tightly regulated during early placentation to stimulate trophoblast invasion and remodel uterine spiral arteries. Access to human 1st and 2nd trimester uterine tissues allowed us to investigate the transcriptional changes in uNK cells during the early stages of early human pregnancy. Microarray analysis identified 97 upregulated genes in 2nd compared to 1st trimester purified uNK cells of which the majority (61%) clustered as interferon-stimulated-genes (ISG), with ISG15 and ISG20 being upregulated profoundly. Type I interferons (IFNα/β), but not type II interferon (IFNɣ) increased expression of the identified interferon target genes ISG15 and ISG20 in uNK cells in vitro. Moreover, the cytokine-like protein ISG15 stimulated in vitro trophoblast invasion. Second trimester uNK cells promoted trophoblast invasion in vitro, whereas both 1st and 2nd trimester uNK cells stimulated endothelial tube formation. IFNα but not IFNβ stimulation of 1st trimester uNK cells enhanced their capacity to promote trophoblast invasion. In conclusion, the uNK cell interferon transcriptome is upregulated during the 2nd trimester allowing uNK cells to promote trophoblast invasion. Type I interferon signaling regulates uNK cell-induced trophoblast invasion via induction of effector molecules like ISG15. First trimester uNK cells can be induced to act like second trimester uNK cells by IFNα with respect to promotion of trophoblast invasion. Key words: Gene expression profiling ■ uterine natural killer cells ■ extravillous trophoblast invasion ■ interferon alpha ■ ISG15
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Project description:Invasion of cytotrophoblasts into uterine tissues is essential for placental development. To identify molecules regulating trophoblast invasion, mRNA signatures of purified villous (CTB, poor invasiveness) and extravillous (EVT, high invasiveness) trophoblasts isolated from first trimester human placentae and villous explant cultures, respectively, were compared using GeneChip analyses yielding 991 invasion/migration related transcripts. Several genes involved in physiological and pathologic cell invasion, including ADAM-12,-19,-28 as well as Spondin-2, were upregulated in EVT. Pathway prediction analyses identified several functional modules associated with either the invasive or the non-invasive trophoblast phenotype. One of the genes which were downregulated in the invasive mRNA pool, heme oxygenase-1 (HO-1), was selected for functional analyses. Real-time PCR analyses, Western blottting, and immunofluorescene of first trimester placentae and differentiating villous explant cultures demonstrated downregulation of HO-1 in invasive EVT as compared to CTB. Modulation of HO-1 expression in loss-of as well as gain-of function cell models (BeWo and HTR8/SVneo, respectively) demonstrated an inverse relationship of HO-1 expression with trophoblast migration in transwell and wound healing assays. Importantly, HO-1 expression led to an increase in protein levels and activity of the nuclear hormone receptor PPARgamma. Pharmacological inhibition of PPARgamma abrogated the inhibitory effects of HO-1 on trophoblast migration. Collectively, our results demonstrate that gene expression profiling of EVT and CTB can be used to unravel novel regulators of cell invasion. Accordingly, we identify heme oxygenase-1 as a negative regulator of trophoblast motility acting via upregulation of PPARgamma. Experiment Overall Design: To identify genes potentially regulating cell invasion trophoblast cells of early human gestation with distinct invasive properties were profiled. Experiment Overall Design: Distinct gene expression signatures of highly invasive EVT (n = 6) and poorly invasive CTB (n = 5) of different first trimester placentae using Affymetrix U133A GeneChips interrogating >20,000 genes were determined.
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