Abstract
Successful embryo implantation and placentation depend on appropriate trophoblast invasion into the maternal endometrial stroma. Human chorionic gonadotropin (hCG) is one of the earliest embryo-derived secreted signals in the peripheral blood mononuclear cells (PBMC) that abundantly expresses hCG receptors. The aims of this study were to estimate the effect of human embryo–secreted hCG on PBMC function and investigate the role and underlying mechanisms of activated PBMC in trophoblast invasion. Blood samples were collected from women undergoing benign gynecological surgery during the mid-secretory phase. PBMC were isolated and stimulated with or without hCG for 0 or 24 h. Interleukin-1β (IL-1β) and leukemia inhibitory factor (LIF) expressions in PBMC were detected by enzyme-linked immunosorbent assay and real-time polymerase chain reaction (PCR). The JAR cell line served as a model for trophoblast cells and was divided into four groups: control, hCG only, PBMC only, and PBMC with hCG. JAR cell invasive and proliferative abilities were detected by trans-well and CCK8 assays and matrix metalloproteinase (MMP)-2 (MMP-2), MMP-9, vascular endothelial growth factor (VEGF), tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 expressions in JAR cells were detected by western blotting and real-time PCR analysis. We found that hCG can remarkably promote IL-1β and LIF promotion in PBMC after 24-h culture. PBMC activated by hCG significantly increased the number of invasive JAR cells in an invasion assay without affecting proliferation, and hCG-activated PBMC significantly increased MMP-2, MMP-9, and VEGF and decreased TIMP-1 and TIMP-2 expressions in JAR cells in a dose-dependent manner. This study demonstrated that hCG stimulates cytokine secretion in human PBMC and could stimulate trophoblast invasion.
Highlights
Successful embryo implantation and placentation depend on the appropriate invasion of fetusderived trophoblasts into the maternal endometrial stroma [1,2,3], a process that is initiated during the mid-secretory phase of the menstrual cycle
A real-time polymerase chain reaction (PCR) assay showed that IL-1β and leukemia inhibitory factor (LIF) transcripts were expressed in human cultured peripheral blood mononuclear cells (PBMC) (Fig 1A and 1B)
Compared with the control and Human chorionic gonadotropin (hCG)-treated groups, matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor (VEGF) mRNA expression levels in 800 or 1600 μL of the culture medium supernatant of PBMC with hCG group normalized by β-actin expression levels were significantly increased (P < 0.05), while tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 mRNA expression levels in the PBMC with hCG group were significantly decreased compared with those in the control and hCGtreated groups (P < 0.05). These results suggest that PBMC activated by hCG may regulate trophoblast invasion by upregulating MMP-2, MMP-9, and VEGF expressions and downregulating TIMP-1 and TIMP-2 expressions
Summary
Successful embryo implantation and placentation depend on the appropriate invasion of fetusderived trophoblasts into the maternal endometrial stroma [1,2,3], a process that is initiated during the mid-secretory phase of the menstrual cycle. An insufficient trophoblastic invasion capacity causes embryo implantation dysfunction, early abortion, preeclampsia, and other complications [4]. At the embryonic implantation site, the human embryo buries within the maternal endometrium by 12 days after ovulation and becomes surrounded by maternal blood, which contains peripheral blood mononuclear cells (PBMC) [5]. Several cytokines and chemokines have been identified as being expressed in and even secreted by fetal cytotrophoblasts and decidual stroma, and the corresponding receptors are expressed in the maternal immune cells [7, 8]. It was speculated that both hCG and immune cells contribute to the cross-talk between mother and embryo [6]
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