Abstract
From the earliest stages of gestation, embryonic–maternal interaction has a key role in a successful pregnancy. Various factors present during gestation may significantly influence this type of juxta/paracrine interaction. PreImplantation Factor (PIF) is a recently identified factor with activity at the fetomaternal interface. PIF is secreted by viable embryos and directly controls placental development by increasing the invasive capacity of human extravillous trophoblasts (EVTs). To further specify PIF's role in the human placenta, we analyzed the genome-wide expression profile of the EVT in the presence of a synthetic PIF analog (sPIF). We found that sPIF exposure altered several pathways related to p53 signaling, survival and the immune response. Functional assays revealed that sPIF acts through the p53 pathway to reduce both early and late trophoblast apoptosis. More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser-15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2-associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels. Furthermore, invalidation experiments of TP53 allowed us to demonstrate that PIF's effects on placental apoptosis seemed to be essentially mediated by this gene. We have clearly shown that p53 and sPIF pathways could interact in human trophoblast and thus promotes cell survival. Furthermore, sPIF was found to regulate a gene network related to immune tolerance in the EVT, which emphasizes the beneficial effect of this peptide on the human placenta. Finally, the PIF protein levels in placentas from pregnancies affected by preeclampsia or intra-uterine growth restriction were significantly lower than in gestational age-matched control placentas. Taken as a whole, our results suggest that sPIF protects the EVT's functional status through a variety of mechanisms. Clinical application of sPIF in the treatment of disorders of early pregnancy can be envisioned.
Highlights
Placentation is a critical step in the establishment of a successful pregnancy
To study the mechanisms possibly affected by treatment with synthetic PIF analog (sPIF), we performed a genome-wide microarray analysis of human extravillous trophoblast (EVT) cultured in the absence or presence of sPIF (50 nM) using an Agilent 8 × 60k microarray
SPIF upregulated the expression of (i) the gene coding for azurocidin-1 (AZU1), a protein with an important role in the chemotactic and antimicrobial activity of monocytes, (ii) the gene coding for olfactory receptor family 10 subfamily A member 7 (OR10A7), (iii) interleukin 17F (IL17F) and (iv) two long intergenic noncoding RNAs
Summary
Placentation is a critical step in the establishment of a successful pregnancy. The placenta is a transitory organ responsible for fetomaternal exchanges and maternal immunotolerance. PIF exerts pro-apoptotic effects and creates a beneficial pro-inflammatory environment.[11,12] PIF orchestrates maternal systemic immune responses.[13] Pathway analysis in models of autoimmunity and transplantation have demonstrated that when administered as a single agent to non-pregnant mice, synthetic PIF analog (sPIF) is associated with a reduction in oxidative stress[8,14] and protein misfolding.[15,16,17,18,19] PIF is expressed by the placenta and by hematopoietic fetal tissues.[13,20] Moindjie et al have recently reported that PIF expression in trophoblastic cells is prominent in the earliest stages of pregnancy and declines at term This observation suggests that endogenous PIF has a significant role in the critical postimplantation phase during which development of the trophoblast must be regulated.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
