Immunohistochemical Study on the Expression of G-CSF, G-CSFR, VEGF, VEGFR-1, Foxp3 in First Trimester Trophoblast of Recurrent Pregnancy Loss in Pregnancies Treated with G-CSF and Controls

Int J Mol Sci. 2019 Dec 31;21(1):285. doi: 10.3390/ijms21010285.


Background: Recurrent Pregnancy Loss (RPL) is a syndrome recognizing several causes, and in some cases the treatment with Granulocyte Colony Stimulating Factor (G-CSF) may be successful, especially when karyotype of the previous miscarriage showed no embryo chromosomal abnormalities. In order to evaluate the effects of G-CSF treatment on the decidual and trophoblast expression of G-CSF and its receptor, VEGF and its receptor and Foxp3, specific marker of putative Tregs we conducted an immunohistochemical study.

Methods: This study was conducted on three groups of patients for a total of 38 women: in 8 cases decidual and trophoblast tissue were obtained from 8 women with unexplained RPL treated with G-CSF that miscarried despite treatment; in 15 cases the tissue were obtained from 15 women with unexplained RPL no treated; 15 cases of women who underwent voluntary pregnancy termination were used as controls. Tissue collected from these patients were used for immunohistochemistry studies testing the expression of G-CSF, G-CSFR, VEGF, VEGFR-1 and Foxp3.

Results: G-CSF treatment increased the concentration of cells expressing Foxp3, specific marker for Tregs, in the decidua, whereas in no treated RPL a reduction of these cells was found when compared to controls. Furthermore, G-CSF treatment increased the expression of G-CSF and VEGF in the trophoblast.

Conclusions: Our study showed that G-CSF treatment increased the number of decidual Treg cells in RPL patients as well as the expression of G-CSF and VEGF in villus trophoblast. These finding may explain the effectiveness of this treatment in RPL, probably regulating the maternal immune response through Tregs recruitment in the decidua, as well as stimulating trophoblast growth.

Keywords: G-CSF; G-CSFR; Treg; VEGF; VEGFR-1 Foxp3; recurrent pregnancy loss.

MeSH terms

  • Abortion, Habitual / metabolism*
  • Abortion, Habitual / pathology
  • Adult
  • Decidua / metabolism
  • Decidua / pathology
  • Female
  • Forkhead Transcription Factors / biosynthesis*
  • Gene Expression Regulation / drug effects*
  • Granulocyte Colony-Stimulating Factor* / administration & dosage
  • Granulocyte Colony-Stimulating Factor* / biosynthesis
  • Humans
  • Immunohistochemistry
  • Pregnancy
  • Pregnancy Trimester, First / metabolism*
  • Receptors, Granulocyte Colony-Stimulating Factor / biosynthesis*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology
  • Trophoblasts / metabolism*
  • Trophoblasts / pathology
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor Receptor-1 / biosynthesis*


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Receptors, Granulocyte Colony-Stimulating Factor
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Granulocyte Colony-Stimulating Factor
  • Vascular Endothelial Growth Factor Receptor-1