Molecular Signaling Regulating Endometrium-Blastocyst Crosstalk

Abstract

Implantation of the embryo into the uterine endometrium is one of the most finely-regulated processes that leads to the establishment of a successful pregnancy. A plethora of factors are released in a time-specific fashion to synchronize the differentiation program of both the embryo and the endometrium. Indeed, blastocyst implantation in the uterus occurs in a limited time frame called the "window of implantation" (WOI), during which the maternal endometrium undergoes dramatic changes, collectively called "decidualization". Decidualization is guided not just by maternal factors (e.g., estrogen, progesterone, thyroid hormone), but also by molecules secreted by the embryo, such as chorionic gonadotropin (CG) and interleukin-1β (IL-1 β), just to cite few. Once reached the uterine cavity, the embryo orients correctly toward the uterine epithelium, interacts with specialized structures, called pinopodes, and begins the process of adhesion and invasion. All these events are guided by factors secreted by both the endometrium and the embryo, such as leukemia inhibitory factor (LIF), integrins and their ligands, adhesion molecules, Notch family members, and metalloproteinases and their inhibitors. The aim of this review is to give an overview of the factors and mechanisms regulating implantation, with a focus on those involved in the complex crosstalk between the blastocyst and the endometrium.

Keywords: Notch; blastocyst; chorionic gonadotropin; cytokines; embryo; endometrium; implantation; progesterone.

Figure 1

Thyroid hormone (TH) supplementation stimulates mouse blastocyst hatching in vitro. (A) Schematic representation of the in vitro model developed to assess TH role in implantation. (a) Co-culture of murine blastocysts and endometrial primary cells as the feeder layer; (b) blastocysts cultured on plastic; and (c) endometrial cells cultured without blastocysts. (B) Representative images of the cultures. Scale bar 50 µm. (C,D) Graphs summarizing the results shown in B: percent of hatched blastocysts after co-culture on endometrial cells (C) or on plastic (D). Reproduced with permission from Piccirilli et al. [223].

Figure 2

Blastocyst apposition, adhesion and invasion. The diagram shows a preimplantation-stage (A, B) and invading (C) blastocyst (about 9 to 10 days after conception) and the processes and factors required for uterine receptivity and blastocyst apposition (A), adhesion (B) and invasion (C). hCG denotes human chorionic gonadotropin, LIF leukemia inhibiting factor, IL-1β interleukin-1 beta, EGF-like growth factors epidermal growth factor-like growth factors, AREG amphiregulin, EREG epiregulin, PG progesterone, COX-2 cyclooxygenase-2, PGE2 prostaglandin E2, CSF-1 colony stimulating factor-1, NOTCH1 Notch receptor 1, OPN osteopontin, MUC-1 mucin-1, MMPs metalloproteinases, EGFL7 epidermal growth factor-like domain 7, MAPK mitogen activated protein kinase, AKT protein kinase B, PA plasminogen activator, TGFβ transforming growth factor beta, TIMPs tissue inhibitor of metalloproteinases, PAI-1 plasminogen activator inhibitor-1.