title: Oxygen regulates human cytotrophoblast migration by controlling chemokine and receptor expression.
abstract: BACKGROUND
  Placental development involves the variation of oxygen supply due to vascular changes and cytotrophoblast invasion. Chemokines and their receptors play an important role during placental formation. Herein, the analysis of the chemokine/receptor pair CXCL12/CXCR4 and further chemokine receptors, such as CCR1, CCR7 and CXCR6 expression in human cytotrophoblasts was conducted.
  
  
  METHODS
  Human cytotrophoblasts were examined directly after isolation or after incubation with different oxygen tensions and a chemical HIF-stimulator for 12 h with realtime PCR, immunoblot, immunohistochemistry. Conditioned media of placental villi, decidua, and endothelial cells was used for ELISA analysis of CXL12. Cytotrophoblast migration assays were conducted applying conditioned media of endothelial cells, a CXCL12 gradient, and different oxygen level. Endometrial and decidual tissue was stained for CXCL12 expression.
  
  
  RESULTS
  An upregulation of CXCL12, CXCR4, CCR1, CCR7 and CXCR6 was observed after cytotrophoblast differentiation. Low oxygen supply upregulated CXCR4, CCR7 and CXCR6, but downregulated CXCL12 and CCR1. In contrast to the HIF associated upregulation of the aforementioned proteins, downregulation of CXCL12 and CCR1 seemed to be HIF independent. Cytotrophoblast migration was stimulated by low oxygen, the application of a CXCL12 gradient and endothelial cell conditioned media. CXCL12 was detected in endometrial vessels, glands and conditioned media of placental and decidual tissue, but not decidual vessels.
  
  
  CONCLUSIONS
  Taken together, oxygen supply and cytotrophoblast differentiation seem to be regulators of chemokine and receptor expression and function in human cytotrophoblasts. Therefore, this system seems to be involved in placental development, directed cytotrophoblast migration in the decidual compartment and a subsequent sufficient supply of the growing fetus.
authors.affiliation: Department of Cell and Tissue Biology, University of California (UCSF), San Francisco, 513 Parnassus Ave, CA 94143, USA; University Düsseldorf, Medical Faculty, Department of Obstetrics, Gynecology and REI (UniKiD), Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address: schanz@unikid.de.
authors.forename: A
authors.initials: A
authors.lastname: Schanz
authors.affiliation: Department of Cell and Tissue Biology, University of California (UCSF), San Francisco, 513 Parnassus Ave, CA 94143, USA; Department of Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: kredhors@stanford.edu.
authors.forename: K
authors.initials: K
authors.lastname: Red-Horse
authors.affiliation: University Düsseldorf, Medical Faculty, Department of Obstetrics, Gynecology and REI (UniKiD), Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address: hess@unikid.de.
authors.forename: A P
authors.initials: AP
authors.lastname: Hess
authors.affiliation: University Düsseldorf, Medical Faculty, Department of Obstetrics, Gynecology and REI (UniKiD), Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address: baston-buest@unikid.de.
authors.forename: D M
authors.initials: DM
authors.lastname: Baston-Büst
authors.affiliation: University Düsseldorf, Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address: christian.heiss@med.uni-duesseldorf.de.
authors.forename: C
authors.initials: C
authors.lastname: Heiss
authors.affiliation: University Düsseldorf, Medical Faculty, Department of Obstetrics, Gynecology and REI (UniKiD), Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address: kruessel@unikid.de.
authors.forename: J S
authors.initials: JS
authors.lastname: Krüssel
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D010100:Oxygen / Q000008:administration & dosage* / Q000378:metabolism; D010929:Placentation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects
chemical_list: D018925:Chemokines; D019707:Receptors, Chemokine; D003676:Deferoxamine; D010100:Oxygen
keywords: Chemokine; Chemokine receptor; Cytotrophoblast; Hypoxia; Placenta