Tissue-Specific Ablation of the LIF Receptor in the Murine Uterine Epithelium Results in Implantation Failure

Abstract

The cytokine leukemia inhibitory factor (LIF) is essential for rendering the uterus receptive for blastocyst implantation. In mice, LIF receptor expression (LIFR) is largely restricted to the uterine luminal epithelium (LE). LIF, secreted from the endometrial glands (GEs), binds to the LIFR, activating the Janus kinase–signal transducer and activation of transcription (STAT) 3 (Jak-Stat3) signaling pathway in the LE. JAK-STAT activation converts the LE to a receptive state so that juxtaposed blastocysts begin to implant. To specifically delete the LIFR in the LE, we derived a line of mice in which Cre recombinase was inserted into the endogenous lactoferrin gene (Ltf-Cre). Lactoferrin expression in the LE is induced by E2, and we demonstrate that Cre recombinase activity is restricted to the LE and GE. To determine the requirement of the LIFR in implantation, we derived an additional mouse line carrying a conditional (floxed) Lifrflx/flx gene. Crossing Ltf-Cre mice with Lifrflx/flx mice generated Lifrflx/Δ:LtfCre/+ females that were overtly normal but infertile. Many of these females, despite repeated matings, did not become pregnant. Unimplanted blastocysts were recovered from the Lifrflx/Δ:LtfCre/+ uteri and, when transferred to wild-type recipients, implanted normally, indicating that uterine receptivity rather than the embryo’s competency is compromised. The loss of Lifr results in both the failure for STAT3 to translocate to the LE nuclei and a reduction in the expression of the LIF regulated gene Msx1 that regulates uterine receptivity. These results reveal that uterine expression of the LIFR is essential for embryo implantation and further define the components of the LIF signaling pathway necessary for effective implantation.

Loss of CDYL Results in Suppression of CTNNB1 and Decreased Endometrial Receptivity

“…Using gene expression microarray analysis, we discovered the downregulation of CDYL mRNA in the endometrial samples obtained from patients with RIF (Figure 1) (Guo et al, 2018). We further detected the significantly lower expression of CDYL protein in the RIF group, consistent with the expression of LIF ( Figure 1C), which is a marker of endometrial receptivity (Paiva et al, 2009;Cheng et al, 2017;Vagnini et al, 2019). In addition, the results obtained from ROC analysis revealed the high sensitivity and specificity to discriminate endometrial receptivity based on the CDYL expression levels of the endometrial tissues.…”

GnRH agonist improves pregnancy outcome in mice with induced adenomyosis by restoring endometrial receptivity

“…One study suggested that uterine receptivity and implantation was regulated by the Lif-Lifr/gp130-JAK/STAT3 signaling pathway. 41 …”

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

“…Despite these limitations, the function of selected cytokines and chemokines in the immunologic interaction between the mother and the trophoblast is being discovered in several cases. For instance, the importance of LIF in early stages of embryo implantation has become clear [120]; moreover, emerging evidence strongly suggests that on the one hand, the major pro-inflammatory cytokines IL-1β and TNF-α, released by uterine macrophages sensitized by seminal fluid antigens, contribute to the development of tolerogenic DCs (tDCs) [54]; on the other hand, after embryo implantation, the anti-inflammatory cytokines IL-10 and TGFβ play key roles in the regulation of tolerogenic DCs in the decidua, in reducing the local inflammatory response and in driving the expansion of Treg cells [33,54]. Among the chemokines, CXCL1 was found to be markedly upregulated in decidualized human endometrial stromal cells [121].…”