The role of leukemia inhibitory factor in tubal ectopic pregnancy

T. Krishnan, A. Winship, S. Sonderegger, E. Menkhorst, A.W. Horne, J. Brown, J.-G. Zhang, N.A. Nicola, S. Tong, E. Dimitriadis

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Introduction: 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 and is present in ectopic implantation sites. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the Fallopian tube, contributing to ectopic pregnancy. Methods: We immunolocalised LIF receptor (R) in tubal ectopic pregnancy (N = 5). We used an oviduct cell line (OE-E6/E7) to model Fallopian tube epithelial cells and a trophoblast spheroid co-culture model (HTR-8/SVneo cell line formed spheroids) to model blastocyst attachment to the Fallopian tube. We examined LIF signaling pathways in OE-E6/E7 cells by Western blot. The effect of LIF and LIF inhibition (using a novel LIF inhibitor, PEGLA) on first-trimester placental outgrowth was determined. Results: 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. LIF stimulated HTR-8/SVneo spheroid adhesion to OE-E6/E7 cells which was significantly reduced after PEGLA treatment. LIF promoted placental explants outgrowth, while co-treatment with PEGLA blocked outgrowth. Discussion: Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth from placental explants. Ectopic pregnancy is usually diagnosed after 6 weeks of pregnancy, therefore PEGLA may be useful in targeting trophoblast growth/invasion. Conclusion: LIF may contribute to the development of ectopic pregnancies and that pharmacologically targeting LIF-mediated trophoblast outgrowth may be useful as a treatment for ectopic pregnancy.
Original languageEnglish
Pages (from-to)1014-1019
Number of pages6
JournalPlacenta
Volume34
Issue number11
DOIs
Publication statusPublished - Nov 2013

Keywords

  • Leukemia inhibitory factor
  • Ectopic
  • Implantation
  • Placenta
  • EVT
  • Pregnancy

Cite this

Krishnan, T. ; Winship, A. ; Sonderegger, S. ; Menkhorst, E. ; Horne, A.W. ; Brown, J. ; Zhang, J.-G. ; Nicola, N.A. ; Tong, S. ; Dimitriadis, E. / The role of leukemia inhibitory factor in tubal ectopic pregnancy. In: Placenta. 2013 ; Vol. 34, No. 11. pp. 1014-1019.
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title = "The role of leukemia inhibitory factor in tubal ectopic pregnancy",
abstract = "Introduction: 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 and is present in ectopic implantation sites. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the Fallopian tube, contributing to ectopic pregnancy. Methods: We immunolocalised LIF receptor (R) in tubal ectopic pregnancy (N = 5). We used an oviduct cell line (OE-E6/E7) to model Fallopian tube epithelial cells and a trophoblast spheroid co-culture model (HTR-8/SVneo cell line formed spheroids) to model blastocyst attachment to the Fallopian tube. We examined LIF signaling pathways in OE-E6/E7 cells by Western blot. The effect of LIF and LIF inhibition (using a novel LIF inhibitor, PEGLA) on first-trimester placental outgrowth was determined. Results: 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. LIF stimulated HTR-8/SVneo spheroid adhesion to OE-E6/E7 cells which was significantly reduced after PEGLA treatment. LIF promoted placental explants outgrowth, while co-treatment with PEGLA blocked outgrowth. Discussion: Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth from placental explants. Ectopic pregnancy is usually diagnosed after 6 weeks of pregnancy, therefore PEGLA may be useful in targeting trophoblast growth/invasion. Conclusion: LIF may contribute to the development of ectopic pregnancies and that pharmacologically targeting LIF-mediated trophoblast outgrowth may be useful as a treatment for ectopic pregnancy.",
keywords = "Leukemia inhibitory factor, Ectopic, Implantation, Placenta, EVT, Pregnancy",
author = "T. Krishnan and A. Winship and S. Sonderegger and E. Menkhorst and A.W. Horne and J. Brown and J.-G. Zhang and N.A. Nicola and S. Tong and E. Dimitriadis",
year = "2013",
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Krishnan, T, Winship, A, Sonderegger, S, Menkhorst, E, Horne, AW, Brown, J, Zhang, J-G, Nicola, NA, Tong, S & Dimitriadis, E 2013, 'The role of leukemia inhibitory factor in tubal ectopic pregnancy', Placenta, vol. 34, no. 11, pp. 1014-1019. https://doi.org/10.1016/j.placenta.2013.09.003

The role of leukemia inhibitory factor in tubal ectopic pregnancy. / Krishnan, T. ; Winship, A.; Sonderegger, S.; Menkhorst, E.; Horne, A.W.; Brown, J.; Zhang, J.-G.; Nicola, N.A.; Tong, S.; Dimitriadis, E.

In: Placenta, Vol. 34, No. 11, 11.2013, p. 1014-1019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The role of leukemia inhibitory factor in tubal ectopic pregnancy

AU - Krishnan, T.

AU - Winship, A.

AU - Sonderegger, S.

AU - Menkhorst, E.

AU - Horne, A.W.

AU - Brown, J.

AU - Zhang, J.-G.

AU - Nicola, N.A.

AU - Tong, S.

AU - Dimitriadis, E.

PY - 2013/11

Y1 - 2013/11

N2 - Introduction: 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 and is present in ectopic implantation sites. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the Fallopian tube, contributing to ectopic pregnancy. Methods: We immunolocalised LIF receptor (R) in tubal ectopic pregnancy (N = 5). We used an oviduct cell line (OE-E6/E7) to model Fallopian tube epithelial cells and a trophoblast spheroid co-culture model (HTR-8/SVneo cell line formed spheroids) to model blastocyst attachment to the Fallopian tube. We examined LIF signaling pathways in OE-E6/E7 cells by Western blot. The effect of LIF and LIF inhibition (using a novel LIF inhibitor, PEGLA) on first-trimester placental outgrowth was determined. Results: 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. LIF stimulated HTR-8/SVneo spheroid adhesion to OE-E6/E7 cells which was significantly reduced after PEGLA treatment. LIF promoted placental explants outgrowth, while co-treatment with PEGLA blocked outgrowth. Discussion: Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth from placental explants. Ectopic pregnancy is usually diagnosed after 6 weeks of pregnancy, therefore PEGLA may be useful in targeting trophoblast growth/invasion. Conclusion: LIF may contribute to the development of ectopic pregnancies and that pharmacologically targeting LIF-mediated trophoblast outgrowth may be useful as a treatment for ectopic pregnancy.

AB - Introduction: 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 and is present in ectopic implantation sites. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the Fallopian tube, contributing to ectopic pregnancy. Methods: We immunolocalised LIF receptor (R) in tubal ectopic pregnancy (N = 5). We used an oviduct cell line (OE-E6/E7) to model Fallopian tube epithelial cells and a trophoblast spheroid co-culture model (HTR-8/SVneo cell line formed spheroids) to model blastocyst attachment to the Fallopian tube. We examined LIF signaling pathways in OE-E6/E7 cells by Western blot. The effect of LIF and LIF inhibition (using a novel LIF inhibitor, PEGLA) on first-trimester placental outgrowth was determined. Results: 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. LIF stimulated HTR-8/SVneo spheroid adhesion to OE-E6/E7 cells which was significantly reduced after PEGLA treatment. LIF promoted placental explants outgrowth, while co-treatment with PEGLA blocked outgrowth. Discussion: Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth from placental explants. Ectopic pregnancy is usually diagnosed after 6 weeks of pregnancy, therefore PEGLA may be useful in targeting trophoblast growth/invasion. Conclusion: LIF may contribute to the development of ectopic pregnancies and that pharmacologically targeting LIF-mediated trophoblast outgrowth may be useful as a treatment for ectopic pregnancy.

KW - Leukemia inhibitory factor

KW - Ectopic

KW - Implantation

KW - Placenta

KW - EVT

KW - Pregnancy

UR - http://www.sciencedirect.com/science/article/pii/S0143400413007297

U2 - 10.1016/j.placenta.2013.09.003

DO - 10.1016/j.placenta.2013.09.003

M3 - Article

VL - 34

SP - 1014

EP - 1019

JO - Placenta

JF - Placenta

SN - 0143-4004

IS - 11

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Krishnan T, Winship A, Sonderegger S, Menkhorst E, Horne AW, Brown J et al. The role of leukemia inhibitory factor in tubal ectopic pregnancy. Placenta. 2013 Nov;34(11):1014-1019. https://doi.org/10.1016/j.placenta.2013.09.003