Murine embryos exposed to human endometrial MSCs-derived extracellular vesicles exhibit higher VEGF/PDGF AA release, increased blastomere count and hatching rates

PLoS One. 2018 Apr 23;13(4):e0196080. doi: 10.1371/journal.pone.0196080. eCollection 2018.

Abstract

Endometrial Mesenchymal Stromal Cells (endMSCs) are multipotent cells with immunomodulatory and pro-regenerative activity which is mainly mediated by a paracrine effect. The exosomes released by MSCs have become a promising therapeutic tool for the treatment of immune-mediated diseases. More specifically, extracellular vesicles derived from endMSCs (EV-endMSCs) have demonstrated a cardioprotective effect through the release of anti-apoptotic and pro-angiogenic factors. Here we hypothesize that EV-endMSCs may be used as a co-adjuvant to improve in vitro fertilization outcomes and embryo quality. Firstly, endMSCs and EV-endMSCs were isolated and phenotypically characterized for in vitro assays. Then, in vitro studies were performed on murine embryos co-cultured with EV-endMSCs at different concentrations. Our results firstly demonstrated a significant increase on the total blastomere count of expanded murine blastocysts. Moreover, EV-endMSCs triggered the release of pro-angiogenic molecules from embryos demonstrating an EV-endMSCs concentration-dependent increase of VEGF and PDGF-AA. The release of VEGF and PDGF-AA by the embryos may indicate that the beneficial effect of EV-endMSCs could be mediating not only an increase in the blastocyst's total cell number, but also may promote endometrial angiogenesis, vascularization, differentiation and tissue remodeling. In summary, these results could be relevant for assisted reproduction being the first report describing the beneficial effect of human EV-endMSCs on embryo development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastomeres / cytology*
  • Blastomeres / physiology
  • Cell Differentiation
  • Coculture Techniques
  • Embryo, Mammalian / metabolism
  • Embryonic Development
  • Endometrium / cytology*
  • Endometrium / metabolism
  • Extracellular Vesicles / physiology*
  • Female
  • Fertilization in Vitro
  • Humans
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / metabolism
  • Platelet-Derived Growth Factor / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Platelet-Derived Growth Factor
  • Vascular Endothelial Growth Factor A
  • platelet-derived growth factor A
  • vascular endothelial growth factor A, mouse

Grants and funding

This work was supported in part by CIBER-CV (CB16/11/00494). One grant from Junta de Extremadura (Ayuda a grupos catalogados de la Junta de Extremadura, GR15175). Two grants from Junta de Extremadura to JGC (TA13042 and IB16168 co-financed by FEDER/FSE). One grant to B-MC (IB16159 co-financed by FEDER/FSE). One grant “Miguel Servet I” from Instituto de Salud Carlos III to JGC (CP17/00021 co-financed by FEDER/FSE). One grant “Juan de la Cierva” to B-MC from Spanish Ministry of Economy, Industry and Competitiveness (IJCI-2014-19428). The funders had no role in study designs, data collection and analysis, decision to publish or preparation of the manuscript.