Hypoxia-induced changes in the bioactivity of cytotrophoblast-derived exosomes

PLoS One. 2013 Nov 11;8(11):e79636. doi: 10.1371/journal.pone.0079636. eCollection 2013.

Abstract

Migration of extravillous trophoblasts (EVT) into decidua and myometrium is a critical process in the conversion of maternal spiral arterioles and establishing placenta perfusion. EVT migration is affected by cell-to-cell communication and oxygen tension. While the release of exosomes from placental cells has been identified as a significant pathway in materno-fetal communication, the role of placental-derived exosomes in placentation has yet to be established. The aim of this study was to establish the effect of oxygen tension on the release and bioactivity of cytotrophoblast (CT)-derived exosomes on EVT invasion and proliferation. CT were isolated from first trimester fetal tissue (n = 12) using a trypsin-deoxyribonuclease-dispase/Percoll method. CT were cultured under 8%, 3% or 1% O2 for 48 h. Exosomes from CT-conditioned media were isolated by differential and buoyant density centrifugation. The effect of oxygen tension on exosome release (µg exosomal protein/10(6)cells/48 h) and bioactivity were established. HTR-8/SVneo (EVT) were used as target cells to establish the effect (bioactivity) of exosomes on invasion and proliferation as assessed by real-time, live-cell imaging (Incucyte™). The release and bioactivity of CT-derived exosomes were inversely correlated with oxygen tension (p<0.001). Under low oxygen tensions (i.e. 1% O2), CT-derived exosomes promoted EVT invasion and proliferation. Proteomic analysis of exosomes identified oxygen-dependent changes in protein content. We propose that in response to changes in oxygen tension, CTs modify the bioactivity of exosomes, thereby, regulating EVT phenotype. Exosomal induction of EVT migration may represent a normal process of placentation and/or an adaptive response to placental hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement
  • Cell Proliferation
  • Exosomes / metabolism*
  • Female
  • Humans
  • Hypoxia / metabolism*
  • Oxygen / metabolism
  • Pregnancy
  • Protein Interaction Maps
  • Proteome
  • Proteomics
  • Signal Transduction
  • Trophoblasts / metabolism*

Substances

  • Proteome
  • Oxygen

Grant support

CS holds a Postdoctoral Fellowship at The University of Queensland Centre for Clinical Research, Brisbane, Australia. GER was in receipt of an NHMRC Principal Research Fellowship. The work described herein was partially funded by a CIEF grant (University of Queensland), a Smart Futures Fund grant (Department of Employment, Economic Development and Innovation, Queensland Government) and a Translating Health Discovery into Clinical Applications SuperScience Award (Department of Industry, Innovation, Science, Research and Tertiary Education, Australian Government). This investigation was supported by CONICYT (ACT-73 PIA, Pasantía Doctoral en el Extranjero BECAS Chile), FONDECYT (1110977). CS holds CONICYT-PhD fellowships and Faculty of Medicine/PUC-PhD fellowships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.