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.
Highlights
Trophoblast cell proliferation, migration and invasion into the endometrium are critical events in the initiation of placental development [1]
To determine whether extravillous trophoblast (EVT) in mice produce Leukemia inhibitory factor (LIF) and LIFR, we co-localized these with cytokeratin-positive trophoblasts in serial sections from wild-type implantation sites at mid-gestation (E13)
In order to determine the role of LIF on trophoblast invasion in vivo, which occurs maximally during mid-gestation from E8-E13 [31], mice were treated with polyethylene glycol (PEG) vehicle control or PEGLA from either E8-10 or E10-13 to block LIF action
Summary
Trophoblast cell proliferation, migration and invasion into the endometrium are critical events in the initiation of placental development [1]. Specialized extravillous trophoblast (EVT) cells migrate and invade into the decidua and remodel the maternal spiral arterioles to create widebore arteries and reduce utero-placental resistance [2]. Inadequate or inappropriate spiral artery remodeling and placentation is thought to be a leading cause of pregnancy complications [3]. Placental development is highly regulated spatially and temporally by numerous factors, such as cytokines produced within the local uterine environment [4]. Such factors can determine the success or failure of pregnancy. LIF is a member of the Interleukin-6 (IL-6) family of cytokines and is a secreted glycoprotein that signals via the LIF receptor α-chain (LIFRα)/gp130 heterodimeric complex to activate the downstream signalling cascade including the JAK-STAT [1, 6,7,8,9] and the extracellular signal regulated kinase (ERK) pathways [10]
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