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ISSN 2052-1472 (online)

Reproduction Abstracts (2014) 1 P028 | DOI: 10.1530/repabs.1.P028

Targeting placental trophoblast leukemia inhibitory factor with a unique inhibitor: a novel treatment strategy for ectopic pregnancy

Amy Winship1, Tara Trishnan1, Ellen Menkhorst1, Andrew W Horne2, Jeremy K Brown2, Jian-Guo Zhang3, Nicos Nicola3, Stephen Tong4 & Eva Dimitriadis1

1MIMR–PHI Institute of Medical Research, Melbourne, Victoria, Australia; 2Edinburgh University, Edinburgh, UK; 3The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; 4University of Melbourne, Melbourne, Victoria, Australia.

Introduction: Ectopic pregnancy is unique to humans and a leading cause of maternal morbidity/mortality however the etiology remains unknown. Leukemia inhibitory factor (LIF) has roles in extravillous-trophoblast adhesion/invasion and is expressed in ectopic pregnancy. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the fallopian tube (FT), contributing to ectopic pregnancy. LIF blockade could serve as a treatment strategy.

Methods: We used an oviduct epithelial cell line-OE-E6/E7 and HTR-8/SVneo cell-line (trophoblast-derived) spheroid co-culture to model blastocyst attachment to the FT. LIF signaling was determined by western blot. The effect of LIF/LIF inhibition (using a unique PEGylated-LIF-antagonist (PEGLA)) on first-trimester placental outgrowth was determined. To demonstrate the effect of LIF blockade to reverse trophoblast invasion in vivo, pregnant mice were administered with PEGLA (500 μg×2/day PEGLA/PEG) on gestation days (D)8–10 or 10–13. Implantation sites at D10/13 were stained with cytokeratin (trophoblast), isolectin-B4 and α-SMA (vascular).

Results and discussion: LIF receptor (R) was immunolocalised to villous and extravillous trophoblast and FT epithelium in ectopic pregnancy. LIF activated STAT3 but not ERK in OE-E6/E7 and stimulated HTR-8/SVneo-spheroid adhesion to OE-E6/E7 which was blocked by PEGLA. LIF promoted placental-explant outgrowth, which was blocked by PEGLA. In mice, PEGLA blocked LIF action, reduced decidua (D10), and reduced placental spongiotrophoblast/labyrinth and vascular cells (D13). Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth in the FT.

Conclusion: Ectopic pregnancy is usually diagnosed after six weeks gestation; pharmacologically targeting LIF-mediated trophoblast-outgrowth may be useful as a novel treatment for ectopic pregnancy.

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