Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice

Abstract

The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion in vitro, however its precise role in trophoblast invasion in vivo is unknown. We hypothesized that LIF would be required for normal trophoblast invasion and spiral artery remodeling in mice. Both LIF and its receptor (LIFRα) co-localized with cytokeratin-positive invasive endovascular extravillous trophoblasts (EVT) in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via administration of our unique LIFRα antagonist, PEGLA, resulted in abnormal trophoblast invasion and impaired spiral artery remodeling compared to PEG control. PEGLA-treated mouse decidual vessels were characterized by retention of α-smooth muscle actin (αSMA)-positive vascular smooth muscle cells (VSMCs), while PEG control decidual vessels were remodelled by cytokeratin-positive trophoblasts. LIF blockade did not alter F4/80-positive decidual macrophage numbers between treatment groups, but resulted in down-regulation of decidual transcript levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10), which are important immune cell activation factors that promote spiral artery remodeling during pregnancy. Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk to enable adequate spiral artery remodeling.

Identification of miRNAs and associated pathways regulated by Leukemia Inhibitory Factor in trophoblastic cell lines

“…LIF and its receptor LIFR are localized in the chorionic villi, decidua and extravillous trophoblast cells (EVTs) of first trimester and term placenta [26]. There, LIF exerts an important role in the regulation of EVT invasion and the communication of trophoblast with decidua and immune cells, which is required for an adequate spiral artery remodeling [27].…”

Identification of miRNAs and associated pathways regulated by Leukemia Inhibitory Factor in trophoblastic cell lines

“…LIF and its receptor LIFR are localized in the chorionic villi, decidua and extravillous trophoblast cells (EVTs) of first trimester and term placenta [26]. There, LIF exerts an important role in the regulation of EVT invasion and the communication of trophoblast with decidua and immune cells, which is required for an adequate spiral artery remodeling [27]. Activation of several signaling pathways by LIF and the resulting biological functions in trophoblastic cells have been described previously by our group and others [17, 28–33].…”

Insufficient Angiogenesis: Cause of Abnormally Thin Endometrium in Subfertile Patients?

“…LIF may also play a critical role in controlling angiogenesis in the placental villi, since human fetal endothelial cells express leukemia inhibitory factor receptor (LIF-R), and mice that lack a functional LIF receptor gene show altered vascular development in the placenta [52]. Inhibition of LIF during mid-gestation impairs trophoblast invasion and spiral artery remodeling during pregnancy in mice [53].…”