Preimplantation Factor (PIF) Promotes Human Trophoblast Invasion1

Abstract

Preimplantation factor (PIF) is a peptide secreted by viable mammalian embryos. Moreover, it can be detected in the circulation of pregnant women. Recently, it was shown that PIF promotes invasion in trophoblast cell lines in vitro. Successful human embryo implantation depends on a deep and highly controlled invasion of extravillous trophoblast (EVT) in the maternal endometrium. Trophoblast invasion is regulated in part by matrix metalloproteinase (MMP) activity and integrin expression. The present study demonstrates the presence of PIF in early pregnancy and characterizes its effects on primary human trophoblast invasion. At the fetomaternal interface, intense PIF labeling by immunohistochemistry was present during early gestation in villous trophoblasts and EVTs. A decrease of labeling was observed at term. Furthermore, PIF significantly promoted invasion of human EVT isolated from first-trimester placenta. The proinvasive regulatory effect of PIF in EVT was associated with 1) increased MMP9 activity and 2) reduced tissue inhibitor of metalloproteinase-1 (TIMP1) mRNA expression. PIF also regulated alpha v and alpha 1 integrin mRNA expressions. Last, the proinvasive effect of PIF appeared to be mediated by the mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), and Janus-kinase signal transducer and activator of transcription (JAK-STAT) signaling pathways. In summary, this work describes the direct, positive effect of PIF on the control of human trophoblastic cell invasion by modulation of MMP/TIMP balance and integrin expression. Moreover, these results suggest that PIF is involved in pathological pregnancies characterized by insufficient or excessive trophoblast invasion.

Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity

“…The involvement of RAC1 and downstream b-catenin role in effective trophoblast invasion by promoting metalloproteinase 9 (MMP-9) was shown [64]. PIF also promoted MMP9 while reducing the inhibitor TIMP1 and regulating integrins expression [42]. Thus, the low PIF expression in preeclampsia and intrauterine growth retardation may lead to the low local MMP-9 expression [42, 46].…”

“…A premature decline in PIF has been associated with preeclampsia and intrauterine growth retardation, thus evidencing the peptide’s important role in maintaining effective placental function [41, 43]. PIF promotes invasion by extra villous cells (EVTs), without affecting these cells’ proliferation [42, 44]. This was shown with transformed trophoblasts and confirmed by using primary human EVTs.…”

“…PIF expression in the placenta is highest shortly post-implantation, and declines around term [20, 25, 42]. A premature decline in PIF has been associated with preeclampsia and intrauterine growth retardation, thus evidencing the peptide’s important role in maintaining effective placental function [41, 43].…”

“…PIF’s effect on EVTs invasion is dependent on increased metalloproteinase 9 and reduction of its inhibitor and integrin regulation. Pathway analysis demonstrated that PIF action is dependent on the MAPK, PI3K, and JAK-STAT pathways [42]. PIF acts on, and its effect is dependent on, critical apoptosis regulating the p53 pathway [46].…”

“…This interaction continues, with PIF and HLA-G present in the circulation in later pregnancy. PIF and HLA-G are expressed by the trophoblast, as PIF is expressed by the viable embryo immediately post-fertilization and by the trophoblast shortly after implantation [23, 42]. Both ligands may therefore play a local regulatory role in trophoblast HLA class I function.…”