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.
Identification of novel trophoblast invasion-related genes: heme oxygenase-1 controls motility via peroxisome proliferator-activated receptor gamma.
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HO-1 inhibits preadipocyte proliferation and differentiation at the onset of obesity via ROS dependent activation of Akt2.
Specimen part
View SamplesExcessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of WAT in obesity involves proliferation and differentiation of adipose precursors (APs), however, the underlying molecular mechanisms remain unclear. Here, we identify Heme Oxygenase-1 (HO-1) as selectively being upregulated in the AP fraction of WAT, upon high-fat diet (HFD) feeding. Specific conditional deletion of HO-1 in APs of Hmox1fl/fl-Pdgfra Cre mice enhanced HFD-dependent visceral AP proliferation and differentiation, upstream of Cebp and PPAR. Opposite effects on human preadipocyte proliferation and differentiation in vitro were observed following HO-1 overexpression. Mechanistically, HO-1 acts upstream of AKT2 via ROS thresholding in mitochondria. Deletion of HO-1 in APs is sufficient to lower blood glucose, insulin and free fatty acid levels as well as liver steatosis during obesity, an effect not seen when HO-1 was conditionally deleted at later stages of adipogenesis using AdipoQ-Cre. Together, our data identify HO-1 as a diet-induced regulator limiting visceral adipose tissue hyperplasia during obesity.
HO-1 inhibits preadipocyte proliferation and differentiation at the onset of obesity via ROS dependent activation of Akt2.
Specimen part
View SamplesExcessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of WAT in obesity involves proliferation and differentiation of adipose precursors (APs), however, the underlying molecular mechanisms remain unclear. Here, we identify Heme Oxygenase-1 (HO-1) as selectively being upregulated in the AP fraction of WAT, upon high-fat diet (HFD) feeding. Specific conditional deletion of HO-1 in APs of Hmox1fl/fl-Pdgfra Cre mice enhanced HFD-dependent visceral AP proliferation and differentiation, upstream of Cebp and PPAR. Opposite effects on human preadipocyte proliferation and differentiation in vitro were observed following HO-1 overexpression. Mechanistically, HO-1 acts upstream of AKT2 via ROS thresholding in mitochondria. Deletion of HO-1 in APs is sufficient to lower blood glucose, insulin and free fatty acid levels as well as liver steatosis during obesity, an effect not seen when HO-1 was conditionally deleted at later stages of adipogenesis using AdipoQ-Cre. Together, our data identify HO-1 as a diet-induced regulator limiting visceral adipose tissue hyperplasia during obesity.
HO-1 inhibits preadipocyte proliferation and differentiation at the onset of obesity via ROS dependent activation of Akt2.
Specimen part
View SamplesWe analysed the genexpression of dental follicle cells (DFCs) after 3 days osteogenic differentiation with BMP2 after transfection with a DLX3 plasmid (pDLX3) and after transfection with an empty plasmid (pEV)
A protein kinase A (PKA)/β-catenin pathway sustains the BMP2/DLX3-induced osteogenic differentiation in dental follicle cells (DFCs).
Specimen part
View SamplesThe goal of the experiment: To characterize the dynamic gene expression profile of engineered human skin in vitro and after grafting, and compare with expression profile of uninjured human skin.
Engineered human skin substitutes undergo large-scale genomic reprogramming and normal skin-like maturation after transplantation to athymic mice.
Specimen part
View SamplesMCF7 and BT474 cell lines were exposed to LTED culture for 0 and 2 days, 6 weeks and 10 months and monitored for changes in gene expression
Clinical instability of breast cancer markers is reflected in long-term in vitro estrogen deprivation studies.
Cell line, Treatment, Time
View SamplesTo determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*.
Development of Resistance to EGFR-Targeted Therapy in Malignant Glioma Can Occur through EGFR-Dependent and -Independent Mechanisms.
Specimen part
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An immediate-late gene expression module decodes ERK signal duration.
Specimen part, Cell line
View SamplesWe integrate experimental data and mathematical modelling to unveil how ERK signal duration is relayed to mRNA dynamics.
An immediate-late gene expression module decodes ERK signal duration.
Cell line
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