Developmental biology of the placenta and the origins of placental insufficiency

Chaddha, Vandana; Viero, Sandra; Huppertz, Berthold; Kingdom, John

doi:10.1016/j.siny.2004.03.006

Cited by 238 publications

(182 citation statements)

References 60 publications

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“…STAT3 had the greatest decrease in relative mRNA levels in FGR compared with control placentae. The strength of our study reported herein was that the cohort of placentae from idiopathic FGR was carefully selected using strict clinical criteria indicative of placental insufficiency and underlying pathology (Salafia 1997, Regnault et al 2002, Chaddha et al 2004, Garcia et al 2007). All the FGR study cases had at least two of the three clinical selection criteria diagnosed on ultrasound and comprised cases from the severe end of the FGR spectrum.…”

Section: Discussionmentioning

confidence: 99%

Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

Borg¹,

Yong²,

Lappas³

et al. 2015

Reproduction

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Abnormal trophoblast function is associated with fetal growth restriction (FGR). The JAK-STAT pathway is one of the principal signalling mechanisms by which cytokines and growth factors modulate cell proliferation, differentiation, cell migration and apoptosis. The expression of placental JAK-STAT genes in human idiopathic FGR is unknown. In this study, we propose the hypothesis that JAK-STAT pathway genes are differentially expressed in idiopathic FGR-affected pregnancies and contribute to abnormal feto-placental growth by modulating the expression of the amino acid transporter SNAT2, differentiation marker CGB/human chorionic gonadotrophin betasubunit (b-hCG) and apoptosis markers caspases 3 and 8, and TP53. Expression profiling of FGR-affected placentae revealed that mRNA levels of STAT3, STAT2 and STAT5B decreased by 69, 52 and 50%, respectively, compared with gestational-age-matched controls. Further validation by real-time PCR and immunoblotting confirmed significantly lower STAT3 mRNA and STAT3 protein (total and phosphorylated) levels in FGR placentae. STAT3 protein was localised to the syncytiotrophoblast (ST) in both FGR and control placentae. ST differentiation was modelled by in vitro differentiation of primary villous trophoblast cells from first-trimester and term placentae, and by treating choriocarcinoma-derived BeWo cells with forskolin in cell culture. Differentiation in these models was associated with increased STAT3 mRNA and protein levels. In BeWo cells treated with siRNA targeting STAT3, the mRNA and protein levels of CGB/b-hCG, caspases 3 and 8, and TP53 were significantly increased, while that of SNAT2 was significantly decreased compared with the negative control siRNA. In conclusion, we report that decreased STAT3 expression in placentae may contribute to abnormal trophoblast function in idiopathic FGR-affected pregnancies.

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Section: Discussionmentioning

confidence: 99%

Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

Borg¹,

Yong²,

Lappas³

et al. 2015

Reproduction

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“…80 Failure to create low-resistance utero-placental arterioles leads to placental hypoperfusion and failure to achieve the local and systemic adaptations required for pregnancy, which interact with the underlying maternal factors, ultimately manifest in these disorders. 81 As PE and FGR are considered to be conditions of trophoblast and placental dysfunction, unravelling the complex mechanisms that underlie the key functions of trophoblasts will ultimately help us to understand defects that contribute to these conditions. The principal trophoblast functions, proliferation, migration, invasion, and differentiation, are cellular functions that also underpin the EMT.…”

Section: Emt Is Implicated In Pathological Pregnanciesmentioning

confidence: 99%

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

Davies

Pollheimer

Yong

et al. 2016

Cell Adhesion & Migration

214

154

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A successful pregnancy depends on the intricate and timely interactions of maternal and fetal cells. Placental extravillous cytotrophoblast invasion involves a cellular transition from an epithelial to mesenchymal phenotype. Villous cytotrophoblasts undergo a partial epithelial to mesenchymal transition (EMT) when differentiating into extravillous cytotrophoblasts and gain the capacity to migrate and invade. This review summarizes our current knowledge regarding known regulators of EMT in the human placenta, including the inducers of EMT, upstream transcription factors that control EMT and the downstream effectors, cell adhesion molecules and their differential expression and functions in pregnancy pathologies, preeclampsia (PE) and fetal growth restriction (FGR). The review also describes the research strategies that were used for the identification of the functional role of EMT targets in vitro. A better understanding of molecular pathways driven by placental EMT and further elucidation of signaling pathways underlying the developmental programs may offer novel strategies of targeted therapy for improving feto-placental growth in placental pathologies including PE and FGR.

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“…3 The synCT, composed of millions of nuclei sharing one common cytoplasm, directs nutrient and gas exchange between maternal and fetal circulations, and serves as the primary endocrine component of the placenta. 4 Its formation, function and continued renewal depends upon vCT fusion with existing synCT, where cellular competence for fusion is initiated by activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. 5,6 PKA directs multiple pathways important in trophoblast fusion, including the expression of the transcription factor glial cell missing 1 (GCM1).…”

mentioning

confidence: 99%

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

et al. 2015

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Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development. Cell Death and Differentiation (2015) 22, 1970-1984 doi:10.1038/cdd.2015 published online 24 April 2015 In mammalian development, the placenta forms the mechanical and physiological link between maternal and fetal circulations. In rodents and higher order primates, including humans, this transfer is achieved through extensive uterine infiltration by fetal-derived cells of epithelial lineage called trophoblasts.1 Trophoblast differentiation is essential for optimal placental function, where the underlying molecular processes regulating specific functions of distinct trophoblast populations are strictly controlled. Defects in trophoblast differentiation associate with impaired placental function and directly impact fetal and maternal health. Within the placenta, progenitor trophoblasts (also called villous cytotrophoblasts; vCTs) overlie a well-defined basal lamina forming an organized, mitotically active epithelial layer. vCT differentiation into an overlying multinucleated structure called the syncytiotrophoblast (synCT) is a key event in placental development. 3 The synCT, composed of millions of nuclei sharing one common cytoplasm, directs nutrient and gas exchange between m...

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Developmental biology of the placenta and the origins of placental insufficiency

Cited by 238 publications

References 60 publications

Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

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