Uterine disorders and pregnancy complications: insights from mouse models

Abstract

Much of our knowledge of human uterine physiology and pathology has been extrapolated from the study of diverse animal models, as there is no ideal system for studying human uterine biology in vitro. Although it remains debatable whether mouse models are the most suitable system for investigating human uterine function(s), gene-manipulated mice are considered by many the most useful tool for mechanistic analysis, and numerous studies have identified many similarities in female reproduction between the two species. This Review brings together information from studies using animal models, in particular mouse models, that shed light on normal and pathologic aspects of uterine biology and pregnancy complications.The uterus: a privileged place for new life Early in the history of medicine, the uterus was considered a root of women's mental health. Hippocrates conceived the term "hysteria" (from the Greek word for uterus, hystera) to explain a femalespecific mental condition originating from perturbation of the uterus (1). We now know that the uterus does not contribute to such psychologic problems, but it remains a compound source of many female-specific pathologic conditions.The uterus is part of the urogenital system, which begins to develop in the embryo soon after gastrulation (a process fundamental for formation of the three embryonic layers). It arises from structures known as the Müllerian ducts (MDs) - a pair of ducts that run down the lateral sides of the embryonic urogenital ridge and form the oviducts, uterus, cervix, and upper portion of the vagina - in a process that requires an intricate interplay of many genes (2). To perform its ultimate reproductive function, the uterus is equipped to undergo a finite number of cycles under the regulation of ovarian sex steroid hormones. During these recurring cycles, the endometrial cells lining the uterine cavity proliferate and then regress but are never depleted and do not proliferate out of the normal range (Figure 1) (3). If this tight regulation is somehow perturbed, conditions in the uterus adversely influence fertility, providing some of the many obstacles that reduce the rate of successful human term pregnancy to only 30% of eggs that contact sperm (4). Chromosomal aberrations are the main reason underlying the low rate of successful human term pregnancies, but other major pregnancy complications that reduce the rate of successful human term pregnancy include ectopic pregnancy, preterm birth, intrauterine growth retardation (IUGR), and preeclampsia (5-7).Ethical issues are a fundamental restriction to the study of human pregnancy, as it is virtually impossible to obtain proper human samples for cellular and molecular studies. Indeed, observations using medical devices and a small number and size of endometrial biopsies have been the primary sources from which information on the pathophysiology of the human endometrium has been gathered. Another restriction to studying human uterine biology is that there is no ideal cell culture system that truly suffices fo...

Autotaxin–lysophosphatidic acid– LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

“…Interestingly, a significant negative correlation of gene expression profiles was observed between T13‐injected uteri and uteri null for either Egfr (a target of HB‐EGF), Bmp2, and Wnt4 (Large et al , 2014; Fig 4B). By upstream analysis using the IPA, we also found a significant positive correlation between genes affected by LPA 3 and E 2 signaling, the latter of which is important for the endometrial proliferation and the establishment of early pregnancy (Lim & Wang, 2010; Ramathal et al , 2010; Cha et al , 2012; Pawar et al , 2015; Table 4). Conversely, there was a negative correlation between genes affected by LPA 3 and an ERα antagonist (fulvestrant; Table 4).…”

“…Thus, treatment of human females with an LPA 3 agonist may increase the pregnancy rate by promoting the endometrial cell growth and increasing the endometrial thickness in IVF. This idea is supported by the facts that expression of Lpar3 in mice is up‐ and down‐regulated by P 4 and E 2 , respectively (Hama et al , 2006) and that the balance of female sex hormones is also critical for establishment of pregnancy in both species (Lim & Wang, 2010; Ramathal et al , 2010; Cha et al , 2012). …”

“…In in vitro fertilization (IVF), endometrial thickness is highly correlated with the success rate of implantation and pregnancy (Noyes et al , 1995; Lim & Wang, 2010). Interestingly, patients with recurrent implantation failure in IVF treatment have reduced LPA 3 levels (Achache et al , 2010).…”

“…Decidualization is a series of uterine morphological changes during early pregnancy which is essential for the following placental formation and fetal development (Lim & Wang, 2010; Ramathal et al , 2010; Cha et al , 2012). In mice, decidualization occurs only in the vicinity of the embryos.…”

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

“…[1][2][3] Similar to many developmental processes, implantation involves an intricate succession of molecular and cellular interactions which must be executed within an optimal time frame. During this period, the acquisition of blastocyst implantation competency is synchronized with the establishment of uterine receptivity.…”