Targeting placental leukemia inhibitory factor in vivo with a unique inhibitor as a novel treatment strategy for ectopic pregnancy. — ASN Events
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  3. Targeting placental leukemia inhibitory factor in vivo with a unique inhibitor as a novel treatment strategy for ectopic pregnancy.

Targeting placental leukemia inhibitory factor in vivo with a unique inhibitor as a novel treatment strategy for ectopic pregnancy. (#243)

Amy Winship 1 , Tara Krishnan 1 , Ellen Menkhorst 1 , Andrew Horne 2 , Jeremy Brown 2 , Stephen Tong 3 4 , Jianguo Zhang 5 , Nick Nicola 5 , Evdokia Dimitriadis 1
  1. MIMR-PHI Institute, Clayton, VIC, Australia
  2. The University of Edinburgh, Edinburgh, Scotland, UK
  3. The University of Melbourne, Melbourne, VIC, Australia
  4. The University of Melbourne, Melbourne, VIC, Australia
  5. Walter and Eliza Hall Institute, Melbourne, VIC, Australia

Ectopic pregnancy is unique to humans and a leading cause of maternal morbidity and mortality. The etiology remains unknown however factors regulating embryo implantation likely contribute. Leukemia inhibitory factor (LIF) has roles in extravillous trophoblast adhesion and invasion during normal placental development and is also present in ectopic implantation sites. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the Fallopian tube, contributing to ectopic pregnancy. LIF blockade could serve as a potential treatment strategy.

LIF receptor (R) was immunolocalised in tubal ectopic pregnancy implantation sites (N=5). An oviduct cell line (OE-E6/E7) and a trophoblast cell line (HTR-8/SVneo; spheroid culture) were used to model blastocyst attachment to the Fallopian tube. LIF signaling pathways in OE-E6/E7 were examined by Western blot. The effect of LIF and LIF inhibition (using PEGylated LIF antagonist; PEGLA) on first-trimester placental outgrowth was determined. To demonstrate that LIF blockade could reverse trophoblast invasion in vivo, pregnant C57BL/6J mice were IP administered with PEGLA (500µg/application PEGLA or PEG control) at 1000h and 1600h on days (D)8-10 or 10-13 of pregnancy (D0: day of plug). Implantation sites collected at D10 or 13 were stained with cytokeratin (trophoblast marker) isolectin-B4 and α-SMA (vascular markers).

LIFR localised to villous and extravillous trophoblast and Fallopian tube epithelium in ectopic pregnancy. LIF activated STAT3 but not the ERK pathway in OE-E6/E7 cells. In vitro, PEGLA inhibited LIF stimulated HTR-8/SVneo spheroid adhesion to OE-E6/E7 cells and explant outgrowth. LIF inhibition in pregnant mice impaired decidualization and placental spongiotrophoblast and labyrinth formation.

Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth from placental explants. In mice, LIF inhibition dramatically altered placental development and trophoblast structure. Ectopic pregnancy is usually diagnosed after 6 weeks of pregnancy, therefore PEGLA may be useful as a treatment for ectopic pregnancy.