3.2.1. LIF Signaling

3.2.1. LIF Signaling Blastocyst apposition is the initial stage representing the first physical contact between the blastocyst and the endometrium, in which the blastocyst finds a site for implantation, guided by the maternal endometrium [232,233]. The site of implantation in the human uterus is usually in the upper and posterior part in the midsagittal plane. During blastocyst apposition, the microvilli placed on the apical surface of trophectoderm interdigitate with the pinopodes localized on the apical surface of the uterine epithelium (Figure 2A). These specialized structures support a stable binding between trophoblast and uterine epithelial cells, so that the plasma membranes of these cells are parallel and separated by a distance of 20 nm [234]. The pinopodes secrete LIF [145]. LIF is a cytokine of the IL-6 family, which in the uterus activates the Janus kinases (JAK)-signal transducer and activator of transcription protein (STAT) pathway, and therefore phosphorylates STAT3, whose activation is required for implantation [235,236]. LIF is indispensable for blastocyst implantation. Mice knockout for LIF are infertile. Although able to develop blastocysts, these mice show implantation failure; ; however successful implantation occurs in surrogate mothers [90]. In Lif-null mice the expression of Blastocyst apposition is the initial stage representing the first physical contact between the blastocyst and the endometrium, in which the blastocyst finds a site for implantation, guided by the maternal endometrium [232,233]. The site of implantation in the human uterus is usually in the upper and posterior part in the midsagittal plane. During blastocyst apposition, the microvilli placed on the apical surface of trophectoderm interdigitate with the pinopodes localized on the apical surface of the uterine epithelium (Figure 2A). These specialized structures support a stable binding between trophoblast and uterine epithelial cells, so that the plasma membranes of these cells are parallel and separated by a distance of 20 nm [234]. The pinopodes secrete LIF [145]. LIF is a cytokine of the IL-6 family, which in the uterus activates the Janus kinases (JAK)-signal transducer and activator of transcription protein (STAT) pathway, and therefore phosphorylates STAT3, whose activation is required for implantation [235,236]. LIF is indispensable for blastocyst implantation. Mice knockout for LIF are infertile. Although able to develop blastocysts, these mice show implantation failure; however successful implantation occurs in surrogate mothers [90]. In Lif-null mice the expression of EGF-like growth factors, such as HB-EGF, AREG, and EREG, which, as previously mentioned, are normally expressed by the luminal epithelium adjacent to the blastocyst and are essential for successful pregnancy, is abolished [237]. Since the defects in decidualization caused by the absence of LIF can be rescued by intrauterine administration of EGF ligand [238], it has been hypothesized that LIF favors blastocyst invasion by reducing the expression of cell–cell junction molecules and proliferation of the stromal cells through activation of EGF signaling pathway [239]. In fertile women, LIF expression increases in the endometrium around the time of implantation, while infertile women express low levels of this factor [240,241].
