Granulocyte-Colony Stimulating Factor related pathways tested on an endometrial ex-vivo model

PLoS One. 2014 Oct 2;9(9):e102286. doi: 10.1371/journal.pone.0102286. eCollection 2014.


Introduction: Recombinant human Granulocyte-Colony Stimulating Factor (rhG-CSF) supplementation seems to be a promising innovative therapy in reproductive medicine, used in case of recurrent miscarriage, embryo implantation failure or thin endometrium, although its mechanisms of action remain unknown. Our aim was to identify possible endometrial pathways influenced by rhG-CSF.

Materials and methods: Hypothetical molecular interactions regulated by G-CSF were designed through a previous large scale endometrial microarray study. The variation of endometrial expression of selected target genes was confirmed in control and infertile patients. G-CSF supplementation influence on these targets was tested on an endometrial ex-vivo culture. Middle luteal phase endometrial biopsies were cultured on collagen sponge with or without rhG-CSF supplementation during 3 consecutive days. Variations of endometrial mRNA expression for the selected targets were studied by RT-PCR.

Results: At the highest dose of rhG-CSF stimulation, the mRNA expression of these selected target genes was significantly increased if compared with their expression without addition of rhG-CSF. The selected targets were G-CSF Receptor (G-CSFR), Integrin alpha-V/beta-3 (ITGB3) implicated in cell migration and embryo implantation, Plasminogen Activator Urokinase Receptor (PLAUR) described as interacting with integrins and implicated in cell migration, Thymidine Phosphorylase (TYMP) implicated in local angiogenesis, CD40 and its ligand CD40L involved in cell proliferation control.

Conclusion: RhG-CSF seems able to influence endometrial expressions crucial for implantation process involving endometrial vascular remodelling, local immune modulation and cellular adhesion pathways. These variations observed in an ex-vivo model should be tested in-vivo. The strict indications or counter indication of rhG-CSF supplementation in reproductive field are not yet established, while the safety of its administration in early pregnancy on early embryogenesis still needs to be demonstrated. Nevertheless, rhG-CSF appears as a promising therapy in some difficult and unsolved cases of reproductive failure. Indications of pre-conceptual rhG-CSF supplementation may derive from a diagnosed lack of endometrial expression of some target genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abortion, Habitual / genetics
  • Abortion, Habitual / pathology
  • Adult
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism
  • CD40 Ligand / genetics
  • CD40 Ligand / metabolism
  • Embryo Implantation / drug effects
  • Endometrium / metabolism*
  • Endometrium / pathology
  • Female
  • Gene Expression Regulation / drug effects
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Humans
  • In Vitro Techniques
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism
  • Male
  • Pregnancy
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Urokinase Plasminogen Activator / genetics
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Thymidine Phosphorylase / genetics
  • Thymidine Phosphorylase / metabolism


  • CD40 Antigens
  • ITGB3 protein, human
  • Integrin beta3
  • PLAUR protein, human
  • RNA, Messenger
  • Receptors, Urokinase Plasminogen Activator
  • Granulocyte Colony-Stimulating Factor
  • CD40 Ligand
  • Thymidine Phosphorylase

Grant support

This work is supported by Grant for Fertility Innovation, 2010, Merck Serono, The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.