Deciphering early sensor and driver properties of the endometrium: contribution of the uterus to pregnancy outcome

Background: Pregnancy involves a continuum of complex biological processes. Each of them can be affected by the environment surrounding the pregnant female (e. g. chemicals, nutrition, stress, infection) and data have focused on gametes quality, early blastocyst development and placental function and their perturbations by environmental insults or embryo biotechnologies. During the pregnancy period spanning the entry of the blastocyst into the uterine cavity to implantation of the embryo, biological functions of the endometrium have also been extensively studied, namely uterine receptivity (controlled by maternal factors) and maternal pregnancy recognition (that requires conceptus-produced signals). Nevertheless, recent data based on experimental perturbations have unveiled unexpected biological properties of the endometrium whose structural organization and functionality during pre-placentation period impact embryo trajectory through epigenetic alterations with subsequent consequences on pregnancy progression and final outcome. Review: A renewed vision of the endometrium is presented in this review. Several features including uterine structure, protracted pre-implantation period, epitheliochorial implantation, a clearly identified signal for pregnancy recognition (interferon-tau), high-throughput analyses tools and original experimental models make ruminants valuable models for detailing the molecular and cellular events taking place in the endometrium before placentation occurs. In ruminants as well as other species, endometrial receptivity is required for embryo implantation and is achieved through biological actions of maternal hormones including ovarian steroids. Among them, progesterone appears as a major factor whose experimental alterations of circulating levels can significantly stimulate or inhibit conceptus elongation. Conceptus growth and survival have also been shown to fail in pregnant ewes lacking endometrial glands (UGKO). In these bovine and ovine models, endometrium exhibits altered gene expression patterns and drives embryo development independently from the quality of donor oocytes. In the context of pregnancy maternal recognition, the presence of the conceptus deeply modifies endometrial transcriptome across various stages of late pre-implantation phase. Acting as a paracrine or an endocrine factor, interferon-tau has been recognized as an indispensable factor for successful implantation through its biological actions on endometrial cells, immune cells and luteal cells. Nevertheless, beyond the global maternal reaction to conceptus secretions, distinct endometrial responses can be elicited by embryos produced by in vivo fertilization, in vitro maturation and in vitro fertilization or somatic cell nuclear transfer. These findings have been confirmed in human when endometrial stromal cells are incubated with normal or compromised embryos but only upon differentiation into decidual cells. Then mammalian endometrium can be considered as an early biosensor of embryos presenting different potentials of post-implantation development. Conclusion: Endometrium appears as a dynamic and reactive tissue. Its persistent or transient epigenetic modifications can dramatically affect pre-implantation embryo development with lasting consequences on later stages of pregnancy, including placentation, foetal development, pregnancy outcome and post-natal health. Developing diagnosis and prognosis tools based on endometrial factors will be valuable with the aims to estimate the reproductive capacity of the mother or to assess the developmental potential of the embryo, particularly when assisted reproductive technologies are applied.