Epidermal growth factor-stimulated extravillous cytotrophoblast motility is mediated by the activation of PI3-K, Akt and both p38 and p42/44 mitogen-activated protein kinases

LaMarca, Heather L.; Dash, Philip R.; Vishnuthevan, Keshika; Harvey, Evelyn; Sullivan, Deborah E.; Morris, Cindy A.; Whitley, Guy

doi:10.1093/humrep/den178

Cited by 60 publications

(53 citation statements)

References 27 publications

(42 reference statements)

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“…Finally, we have used EGF to obtain STBs and iCTBs from BMP-treated hESCs. EGF has been shown to promote the formation of iCTBs and STBs from human placental trophoblasts (63)(64)(65)(66). Therefore, our observations are consistent with the behavior of primary human trophoblasts.…”

Section: Discussionsupporting

confidence: 88%

“…Activin treatment causes fusion in trophoblasts (59). Also, EGF promotes the formation of iCTBs and STBs from human placental trophoblasts (63)(64)(65)(66). We report that hESC-derived trophoblasts behave similarly (i.e.…”

Section: Discussionmentioning

confidence: 80%

“…However, primary trophoblasts have been routinely isolated and passaged into cultures containing activin/nodal ligands, EGF, etc. (63)(64)(65)(66), leading to specific cell fates. Thus, our protocols are analogous to these reported protocols but utilizing hESC-derived trophoblasts.…”

Section: Discussionmentioning

confidence: 99%

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Activin/Nodal Signaling Switches the Terminal Fate of Human Embryonic Stem Cell-derived Trophoblasts

Sarkar

Randall

Collier

et al. 2015

Journal of Biological Chemistry

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Background: Specification of terminal fate in trophoblasts derived from human embryonic stem cells is not understood. Results: Inhibition of activin/nodal signaling triggers extravillous fate, but loss of inhibition causes syncytial fate. Conclusion: Activin/nodal signaling switches the terminal fate of trophoblasts. Significance: We provide a model system that allows for targeted derivation of extravillous trophoblasts and syncytiotrophoblasts.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 80%

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Activin/Nodal Signaling Switches the Terminal Fate of Human Embryonic Stem Cell-derived Trophoblasts

Sarkar

Randall

Collier

et al. 2015

Journal of Biological Chemistry

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“…35 EGF expression is most pronounced in the first trimester placenta and is reduced closer to term, suggesting an association of EGF with the early stages of placental development. 36 EGF promotes trophoblast proliferation and differentiation in vitro, 37 and stimulates trophoblast migration in EVT cell lines, 38,39 which involve pathways such as AKT-mediated signaling. 40 During EVT formation, cells downregulate EGFR1 and induce ERBB2 (also termed HER-2/neu) in a similar manner to tumor cells.…”

Section: Inducers Of Emtmentioning

confidence: 99%

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

Davies

Pollheimer

Yong

et al. 2016

Cell Adhesion & Migration

209

146

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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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“…[31][32][33] Of these, the two pathways that are frequently used by trophoblast cells are the Jak-Stat and MAPK pathways. 33 The human MAPK signaling pathway PCR array was used in this study.…”

Section: Hlx Inactivation Impairs Cd34mentioning

confidence: 99%

Downstream Targets of Homeobox Gene HLX Show Altered Expression in Human Idiopathic Fetal Growth Restriction

Rajaraman

Murthi

Pathirage

et al. 2010

The American Journal of Pathology

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Fetal growth restriction (FGR) , a clinically significant pregnancy disorder , is poorly understood at the molecular level. This study investigates idiopathic FGR associated with placental insufficiency. Previously, we showed that the homeobox gene HLX is expressed in placental trophoblast cells and that HLX expression is significantly decreased in human idiopathic FGR. Here , we used the novel approach of identifying downstream targets of HLX in cell culture to detect potentially important genes involved in idiopathic FGR. Downstream targets were revealed by decreasing HLX expression in cultured trophoblast cells with HLX-specific small interfering RNAs to model human idiopathic FGR and comparing these levels with controls using a real-time PCR-based gene profiling system. Changes in candidate HLX target mRNA levels were verified in an independent trophoblast cell line, and candidate target gene expression was assessed in human idiopathic FGR-affected placentae (n ‫؍‬ 25) compared with gestation-matched controls (n ‫؍‬ 25). The downstream targets RB1 and MYC , cell cycle regulatory genes , showed significantly increased mRNA levels in FGR-affected tissues compared with gestation-matched controls , whereas CCNB1 , ELK1 , JUN , and CDKN1 showed significantly decreased mRNA levels (n ‫؍‬ 25 , P < 0.001 , t-test). The changes for RB1 and CDKN1C were verified by Western blot analysis in FGR-affected placentae compared with gestation-matched controls (n ‫؍‬ 6). We conclude that cell cycle regulatory genes RB1 , MYC , CCNB1 , ELK1 , JUN , and CDKN1C , which control important trophoblast cell functions , are targets of HLX. (Am J

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Epidermal growth factor-stimulated extravillous cytotrophoblast motility is mediated by the activation of PI3-K, Akt and both p38 and p42/44 mitogen-activated protein kinases

Abstract: We demonstrate a role for PI3-K, p42/44 MAPK and p38 MAPK in the stimulation of CTB cell motility by EGF, however activation of beta-catenin alone was insufficient to stimulate cell motility.

Cited by 60 publications

References 27 publications

Activin/Nodal Signaling Switches the Terminal Fate of Human Embryonic Stem Cell-derived Trophoblasts

Activin/Nodal Signaling Switches the Terminal Fate of Human Embryonic Stem Cell-derived Trophoblasts

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

Downstream Targets of Homeobox Gene HLX Show Altered Expression in Human Idiopathic Fetal Growth Restriction

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