CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties

Kipkeew, Friederike; Kirsch, Manuela; Klein, Diana; Wuelling, Manuela; Winterhager, Elke; Gellhaus, Alexandra

doi:10.1080/19336918.2016.1139265

Cited by 28 publications

(28 citation statements)

References 59 publications

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“…They mediate endothelial cell growth, adhesion, migration, and survival as well as tumor growth and angiogenesis. Notably, CTGF and CYR61 knockout mice exhibit vascular defects during embryogenesis and fetal development [52], and reduced levels of CYR61 were found in early-onset pre-eclampsia [53]. Interestingly, in a mouse retinal neovascularization model, knocking down CYR61 resulted in a reduction in neovascularization [54].…”

Section: Discussionmentioning

confidence: 99%

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

Lee

Kroener

et al. 2016

Biology of Reproduction

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Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3. Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.

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Section: Discussionmentioning

confidence: 99%

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

Lee

Kroener

et al. 2016

Biology of Reproduction

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“…To measure proliferation, cells were seeded in 96-well plates coated with gelatin at a density of 10,000 cells/well and cultured for 12 h. Then, cells were stimulated with or without hyperIL-6 for 12 h, before adding fresh stimulation medium containing BrdU for additional 24 h. Detection of incorporated BrdU was measured following the manufacturers' protocol (#11 647 229 001, Roche, Mannheim, Germany). For assessing cell senescence, we seeded 10,000 cells/well in a gelatin-coated 96-well plate and incubated the cells for 12 h. Then, hyper-IL-6 stimulation was performed for 48 h. Senescence-associated beta-galactosidase activity was detected by a protocol published by [30]. Finally, tube formation capacity was assayed by a classical tube formation assay.…”

Section: Cell Culture Assaysmentioning

confidence: 99%

Effect of Maternal Obesity in Mice on IL-6 Levels and Placental Endothelial Cell Homeostasis

et al. 2020

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Obesity during pregnancy is a known health risk for mother and child. Since obesity is associated with increased inflammatory markers, our objectives were to determine interleukin-6 (IL-6) levels in obese mice and to examine the effect of IL-6 on placental endothelial cells. Placentas, blood, and adipose tissue of C57BL/6N mice, kept on high fat diet before and during pregnancy, were harvested at E15.5. Serum IL-6 levels were determined and endothelial cell markers and IL-6 expression were measured by qRT-PCR and western blot. Immunostaining was used to determine surface and length densities of fetal capillary profiles and placental endothelial cell homeostasis. Human placental vein endothelial cells were cultured and subjected to proliferation, apoptosis, senescence, and tube formation assays after stimulation with hyperIL-6. Placental endothelial cell markers were downregulated and the percentage of senescent endothelial cells was higher in the placental exchange zone of obese dams and placental vascularization was strongly reduced. Additionally, maternal IL-6 serum levels and IL-6 protein levels in adipose tissue were increased. Stimulation with hyperIL-6 provoked a dose dependent increase of senescence in cultured endothelial cells without any effects on proliferation or apoptosis. Diet-induced maternal obesity led to an IUGR phenotype accompanied by increased maternal IL-6 serum levels. In the placenta of obese dams, this may result in a disturbed endothelial cell homeostasis and impaired fetal vasculature. Cell culture experiments confirmed that IL-6 is capable of inducing endothelial cell senescence.

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“…CCN3 belongs to the ECM CCN family of proteins (CCN1-6) that share a modular structure including of conserved cysteine knot C-terminal (CT) domain and are multi-functional regulators of diverse processes including development, osteogenesis, and angiogenesis [44]. The Notch regulatory activity of CCN3 appears to be important for controlling a variety of activities including osteoblast differentiation [45, 46] and trophoblast senescence [47, 48]. Regulation of Notch signaling may be a general feature of the CCN family since CCN2 (CTGF) suppresses Notch signaling [49] and CCN1 (Cyr61) is linked to suppression of Notch1 during the epithelial to mesenchymal transition (EMT) [50].…”

Section: Direct Ecm-notch Interactions That Control Notch Signalingmentioning

confidence: 99%

Notch: A multi-functional integrating system of microenvironmental signals

LaFoya

Munroe

Mia

et al. 2016

Developmental Biology

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The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.

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CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties

Cited by 28 publications

References 59 publications

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

Effect of Maternal Obesity in Mice on IL-6 Levels and Placental Endothelial Cell Homeostasis

Notch: A multi-functional integrating system of microenvironmental signals

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