Blocking Endogenous Leukemia Inhibitory Factor During Placental Development in Mice Leads to Abnormal Placentation and Pregnancy Loss.
The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Specialized trophoblast cells derived from the embryonic trophectoderm play a pivotal role in the establishment of the placenta. Leukemia inhibitory factor (LIF) is one of the predominant cytokines present in the placenta during early pregnancy. LIF has been shown to regulate trophoblast adhesion and invasion in vitro, however its precise role in vivo is unknown. We hypothesized that LIF would be required for normal placental development in mice. LIF and LIFRα were immunolocalized to placental trophoblasts and fetal vessels in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via intraperitoneal administration of our specific LIFRα antagonist, PEGLA, resulted in abnormal placental trophoblast and vascular morphology and reduced activated STAT3 but not ERK. Numerous genes regulating angiogenesis and oxidative stress were altered in the placenta in response to LIF inhibition. Pregnancy viability was also significantly compromised in PEGLA treated mice. Our data suggest that LIF plays an important role in placentation in vivo and the maintenance of healthy pregnancy.
1] MIMR-PHI Institute of Medical Research, 27-31 Wright St, Clayton, VIC, 3168, Australia [2] Department of Anatomy and Developmental Biology, Wellington Road, Monash University, Clayton, Victoria, 3800, Australia.
Amy
A
Winship
MIMR-PHI Institute of Medical Research, 27-31 Wright St, Clayton, VIC, 3168, Australia.
Jeanne
J
Correia
1] MIMR-PHI Institute of Medical Research, 27-31 Wright St, Clayton, VIC, 3168, Australia [2] Faculty of Medicine, Nursing &Health Sciences, Wellington Road, Monash University, Clayton, Victoria, 3800, Australia.
Tara
T
Krishnan
MIMR-PHI Institute of Medical Research, 27-31 Wright St, Clayton, VIC, 3168, Australia.
Ellen
E
Menkhorst
MIMR-PHI Institute of Medical Research, 27-31 Wright St, Clayton, VIC, 3168, Australia.
Carly
C
Cuman
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Jian-Guo
JG
Zhang
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Nicos A
NA
Nicola
1] MIMR-PHI Institute of Medical Research, 27-31 Wright St, Clayton, VIC, 3168, Australia [2] Department of Anatomy and Developmental Biology, Wellington Road, Monash University, Clayton, Victoria, 3800, Australia.
Evdokia
E
Dimitriadis
D000022:Abortion, Spontaneous / Q000503:physiopathology*; D000818:Animals; D005260:Female; D053605:Leukemia Inhibitory Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010922:Placenta Diseases / Q000503:physiopathology*; D010929:Placentation; D011092:Polyethylene Glycols / Q000494:pharmacology; D011247:Pregnancy; D053606:Receptors, OSM-LIF / Q000037:antagonists & inhibitors
D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D053606:Receptors, OSM-LIF; C525879:pegylated MH35-BD-Q29A+G124R protein; D011092:Polyethylene Glycols