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GDF-11 stimulates human extravillous trophoblast cell invasion by upregulating ANGPTL4 expression

ABSTRACT: Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Growth differentiation factor 11 (GDF-11), a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to promote EVT cell invasion, yet the underlying molecular mechanisms remain largely unclear. In this study, RNA sequencing identified angiopoietin-like 4 (ANGPTL4), a multifunctional secreted protein, as a novel downstream target of GDF-11. In vitro experiments demonstrated that GDF-11 significantly upregulated ANGPTL4 expression in both HTR-8/SVneo cells and primary human EVT cells. Mechanistically, we found that the type I TGF-β receptors ALK4 and ALK5 were essential for mediating the stimulatory effect of GDF-11 on ANGPTL4 expression. Further analysis revealed that SMAD3, but not SMAD2, was the key transcription factor involved in this process. Using both loss- and gain-of-function approaches, we demonstrated that ANGPTL4 was required for GDF-11-induced EVT cell invasion. Importantly, serum levels of GDF-11 were markedly reduced in patients with preeclampsia (PE), a pregnancy disorder associated with shallow trophoblast invasion and poor placentation. Together, our findings uncover a previously unrecognized GDF-11-ANGPTL4 signaling axis that regulates EVT cell invasion and provide new insight into the pathophysiology of PE.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305973 | GEO | 2025/10/21

REPOSITORIES: GEO

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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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GDF-11 stimulates human extravillous trophoblast cell invasion by upregulating ANGPTL4 expression

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