Fibroblast activation during decidualization: Embryo-derived TNFα induction of PGI2-PPARδ-ACTIVIN A pathway through luminal epithelium

Abstract

ObjectivesHuman endometrium undergoes cyclical shedding and bleeding, scar-free repair and regeneration in subsequent cycles. Fibroblast activation has been shown to play a key role during normal tissue repair and scar formation. Abnormal fibroblast activation leads to fibrosis. Fibrosis is the main cause of intrauterine adhesion, uterine scaring, and thin endometrium. Endometrial decidualization is a critical step during early pregnancy. There are 75% of pregnancy failures pointed to decidualization defects. Because fibroblast activation and decidualization share similar markers, we assumed that fibroblast activation should be involved in decidualization. Materials and MethodsBoth pregnant and pseudopregnant ICR mice were used in this study. Immunofluorescence and immunohistochemistry were applied to examine fibroblast activation-related markers in mouse uteri. Western blotting was used to identify the impact on decidualization. Western blot and RT were used to show how arachidonic acid and its downstream product prostaglandin activate fibroblasts. Additionally, embryo-derived TNF was shown to stimulate the secretion of arachidonic acid by immunofluorescence, western blot, and ELASA. The aborted decidual tissues with fetal trisomy 16 were compared with control tissues. GraphPad Prism5.0 Students t test was used to compare differences between control and treatment groups ResultsFibroblast activation-related markers are obviously detected in pregnant decidua and under in vitro decidualization. ACTIVIN A secreted under fibroblast activation promotes in vitro decidualization. We showed that arachidonic acid released from uterine luminal epithelium can induce fibroblast activation and decidualization through PGI2 and its nuclear receptor PPAR-{delta}. Based on the significant difference of fibroblast activation-related markers between pregnant and pseudopregnant mice, we found that embryo-derived TNF promotes cPLA2 phosphorylation and arachidonic acid release from luminal epithelium. Fibroblast activation is also detected under human in vitro decidualization. Similar arachidonic acid-PGI2-PPAR{delta}-ACTIVIN A pathway is conserved in human endometrium. Compared to controls, fibroblast activation is obviously compromised in human decidual tissues with fetal trisomy 16. ConclusionsEmbryo-derived TNF promotes cPLA2 phosphorylation and arachidonic acid release from luminal epithelium to induce fibroblast activation and decidualization. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=144 HEIGHT=200 SRC="FIGDIR/small/509003v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@97b4edorg.highwire.dtl.DTLVardef@1e758d6org.highwire.dtl.DTLVardef@1797acaorg.highwire.dtl.DTLVardef@6c8b82_HPS_FORMAT_FIGEXP M_FIG C_FIG