Abstract
Adequate differentiation or decidualization of endometrial stromal cells (ESC) is critical for successful pregnancy in humans and rodents. Here, we investigated the role of leukemia inhibitory factor (LIF) in human and murine decidualization. Ex vivo human (H) ESC decidualization was induced by estrogen (E, 10−8 M) plus medroxyprogesterone acetate (MPA, 10−7 M). Exogenous LIF (≥50 ng/ml) induced STAT3 phosphorylation in non-decidualized and decidualized HESC and enhanced E+MPA-induced decidualization (measured by PRL secretion, P<0.05). LIF mRNA in HESC was down-regulated by decidualization treatment (E+MPA) whereas LIF receptor (R) mRNA was up-regulated, suggesting that the decidualization stimulus ‘primed’ HESC for LIF action, but that factors not present in our in vitro model were required to induce LIF expression. Ex vivo first trimester decidual biopsies secreted >100 pg/mg G-CSF, IL6, IL8, and MCP1. Decidualized HESC secreted IL6, IL8, IL15 and MCP1. LIF (50 ng/ml) up-regulated IL6 and IL15 (P<0.05) secretion in decidualized HESC compared to 0.5 ng/ml LIF. In murine endometrium, LIF and LIFR immunolocalized to decidualized stromal cells on day 5 of gestation (day 0 = day of plug detection). Western blotting confirmed that LIF and the LIFR were up-regulated in intra-implantation sites compared to inter-implantation sites on Day 5 of gestation. To determine the role of LIF during in vivo murine decidualization, intra-peritoneal injections of a long-acting LIF antagonist (PEGLA; 900 or 1200 µg) were given just post-attachment, during the initiation of decidualization on day 4. PEGLA treatment reduced implantation site decidual area (P<0.05) and desmin staining immuno-intensity (P<0.05) compared to control on day 6 of gestation. This study demonstrated that LIF was an important regulator of decidualization in humans and mice and data provides insight into the processes underlying decidualization, which are important for understanding implantation and placentation.
Highlights
Successful implantation of a blastocyst and subsequent formation of a functional placenta leading to the establishment of pregnancy in women, is dependent on the adequate decidualization of endometrial stromal cells (ESC) [1]
Leukemia inhibitory factor (LIF) immunoreactivity was found in the endometrial stroma during the mid-late secretory phase, in decidualized stromal cells located near spiral arterioles and endothelial cells (Figure 1A)
The LIFR localised to the glandular epithelium and in decidualized stromal cells in the mid-late secretory phase endometrium and in first trimester decidua (Figure 1C & D)
Summary
Successful implantation of a blastocyst and subsequent formation of a functional placenta leading to the establishment of pregnancy in women, is dependent on the adequate decidualization of endometrial stromal cells (ESC) [1]. Decidualization is initiated during the mid-late secretory phase by progesterone, independent of the presence of an implanting blastocyst, the decidua of pregnancy is only formed following blastocyst implantation. In rodents decidualization begins only following implantation of a blastocyst into the endometrium of a hormonally primed uterus. The critical molecular interactions that regulate decidualization are largely unknown, it has been shown that, in addition to ovarian hormones, locally and temporally produced products such as cytokines and growth factors Leukemia inhibitory factor (LIF), an IL6-type cytokine, is one of a very few cytokines shown to be critical for implantation in mice [3]. LIF mRNA and protein is maximally expressed in the murine endometrial glandular epithelium just prior to blastocyst implantation [4,5]: LIF2/2 female mice are infertile due to implantation failure: blastocysts cannot adhere to the endometrial luminal epithelium [6]
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