title: Oxygen tension regulates the miRNA profile and bioactivity of exosomes released from extravillous trophoblast cells - Liquid biopsies for monitoring complications of pregnancy.
abstract: Our understanding of how cells communicate has undergone a paradigm shift since the recent recognition of the role of exosomes in intercellular signaling. In this study, we investigated whether oxygen tension alters the exosome release and miRNA profile from extravillous trophoblast (EVT) cells, modifying their bioactivity on endothelial cells (EC). Furthermore, we have established the exosomal miRNA profile at early gestation in women who develop pre-eclampsia (PE) and spontaneous preterm birth (SPTB). HTR-8/SVneo cells were used as an EVT model. The effect of oxygen tension (i.e. 8% and 1% oxygen) on exosome release was quantified using nanocrystals (Qdot®) coupled to CD63 by fluorescence NTA. A real-time, live-cell imaging system (Incucyte™) was used to establish the effect of exosomes on EC. Plasma samples were obtained at early gestation (<18 weeks) and classified according to pregnancy outcomes. An Illumina TrueSeq Small RNA kit was used to construct a small RNA library from exosomal RNA obtained from EVT and plasma samples. The number of exosomes was significantly higher in EVT cultured under 1% compared to 8% oxygen. In total, 741 miRNA were identified in exosomes from EVT. Bioinformatic analysis revealed that these miRNA were associated with cell migration and cytokine production. Interestingly, exosomes isolated from EVT cultured at 8% oxygen increased EC migration, whilst exosomes cultured at 1% oxygen decreased EC migration. These changes were inversely proportional to TNF-α released from EC. Finally, we have identified a set of unique miRNAs in exosomes from EVT cultured at 1% oxygen and exosomes isolated from the circulation of mothers at early gestation, who later developed PE and SPTB. We suggest that aberrant exosomal signalling by placental cells is a common aetiological factor in pregnancy complications characterised by incomplete SpA remodeling and is therefore a clinically relevant biomarker of pregnancy complications.
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Grace
authors.initials: G
authors.lastname: Truong
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Dominic
authors.initials: D
authors.lastname: Guanzon
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Vyjayanthi
authors.initials: V
authors.lastname: Kinhal
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Omar
authors.initials: O
authors.lastname: Elfeky
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lai
authors.affiliation: Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Ochsner Clinic Foundation, New Orleans, United States of America.
authors.forename: Sherri
authors.initials: S
authors.lastname: Longo
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Zarin
authors.initials: Z
authors.lastname: Nuzhat
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Palma
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Katherin
authors.initials: K
authors.lastname: Scholz-Romero
authors.affiliation: Division of Maternal-Fetal Medicine & Perinatal Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.affiliation: Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine, University of Adelaide, North Adelaide, Australia.
authors.forename: Ben W
authors.initials: BW
authors.lastname: Mol
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.|Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Ochsner Clinic Foundation, New Orleans, United States of America.|Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Rice
authors.affiliation: Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia.|Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Ochsner Clinic Foundation, New Orleans, United States of America.|Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Salomon
mesh_terms: D000328:Adult; D001158:Arteries / Q000378:metabolism; D001706:Biopsy / Q000379:methods; D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000378:metabolism; D016000:Cluster Analysis; D055354:Exosomes / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D046529:Microscopy, Electron, Transmission; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014599:Uterus / Q000098:blood supply
chemical_list: D035683:MicroRNAs; D010100:Oxygen