胚胎植入的调控机理

胚胎植入对于妊娠的建立和维持至关重要,需要活化的胚泡和接受态的子宫之间进行同步。在辅助生殖技术中,子宫接受态的判断仍是制约妊娠率的一个关键限制性因素。已有数据显示,胚胎植入涉及一系列信号分子的激活和失活,进而影响子宫腔上皮细胞的增殖与分化、上皮极性、宫腔闭合、胚胎定位、上皮基质反应、腺体发育等。本文就雌激素、孕酮、白血病抑制因子(leukemia inhibitory factor, LIF)、microRNA (miRNA)、通道蛋白、信号转导通路等在胚胎植入过程中的作用及其调控网络作一综述,以期为不孕症的治疗及安全有效的避孕药开发提供理论依据。     

人类胚胎植入过程中的细胞黏附分子(英文)

人类胚胎植入过程不仅受到在进化上保守的机制调节,而且也受到人类一种独有的机制调节。有证据显示,细胞黏附分子L-选择蛋白和trophinin在人类胚胎植入过程扮演独特的角色。在本文中,我们描述了L-选择素和trophinin的黏蛋白糖配体的双重作用,也描述了trophinin相关蛋白bystin和tastin的双重作用。我们随后描述了滋养外胚层细胞和子宫内膜上皮细胞中由trophinin调节的信号转导。本综述也涵盖了钙依粘连蛋白和整合素在人类胚胎植入过程中的作用。     

胚胎的宫内和异位植入

胚胎植入是一个十分复杂的过程, 被认为是调控女性生育和发展避孕方法最理想的靶点和关键薄弱环节. 近几年, 该领域研究取得一定进展. 然而, 临床上的异位植入对胚胎正常植入的许多理论问题, 特别是对所谓的子宫“特异植入窗口”和子宫内膜-胚胎“特异对话”的概念提出了挑战. 在腹腔异位妊娠病例中, 少部分比例的妇女能完成全部妊娠过程, 生下发育正常的婴儿, 引起生殖生物学家的特别兴趣. 异位植入的事实表明, 对胚胎植入起决定作用的基因或分子可能不是来自母体, 而是来自胚胎, 母体组织只提供了胚胎发育的载体. 在加强正常和异常情况下胚胎植入细胞和分子生物学研究的基础上, 寻找和确定控制着床的内源和外源关键特异分子, 可为有效发展新一代抗胚胎植入特异避孕药物及寻找诊断和治疗异位妊娠提供理论依据.     

胚胎植入与肿瘤浸润转移的相似性

胚胎植入依赖于胚胎滋养层细胞对子宫内膜的侵入,其过程与肿瘤细胞的浸润转移极为相似;（１）它们具有相似的基质侵入行为,并用同种蛋白水解酶降解类似的细胞外基质结构;（２）生长因子对这两种细胞可能具有相似的调节作用;（３）胚胎滋养层细胞和肿瘤细胞的免疫学特性类似,并可能具有共同的免疫逃脱机制,胚胎植入和肿瘤浸润的相似性提示,学科间的交叉,渗透和相互借鉴对生物学基础理论的研究具有重要意义。     

小鼠植入前胚胎致密化与囊胚形成的分子调控

哺乳动物胚胎植入前的发育中致密化和囊胚形成分别标志着第一次、第二次细胞分化（即细胞命运决定）的起始,是胚胎正常发育的必要条件。因此对影响致密化和囊胚形成的蛋白及调节因子的研究尤为重要。本文探讨了与致密化相关的细胞黏附蛋白、连接蛋白、细胞骨架等分子和囊胚形成相关的紧密连接蛋白、钠钾三磷酸腺苷激酶等分子的一系列调控,以及致密化和囊胚形成在细胞命运决定中的重要作用。     

哺乳动物滋养层细胞在胚胎植入中的作用

胚胎植入是哺乳动物生殖的关键环节,是一个非常复杂的过程.在胚胎植入过程中,多种着床相关因子、激素在母体-胚胎之间进行多重作用,引发复杂的生理作用,从而完成胚胎着床.在母体-胚胎界面上,胎源性滋养层细胞与母体子宫内膜细胞在信号联系（妊娠识别）和组织紧密连接（胚胎植入）过程中起着决定性作用,尤其是胚源性滋养层细胞,在胚胎植入过程中起主导作用.本文通过对滋养层细胞在胚胎植入中的作用的阐述,为进一步阐明胚胎植入的分子机制提供思路.     

运用PCR对小鼠植入前胚胎进行性别诊断

根据C57BL6小鼠Y染色体重复序列145C5的碱基顺序,设计并合成一对引物,运用PCR扩增昆明白小鼠入前胚胎卵裂球DNA,以确定其性别,共对108枚活检胚胎的相应卵裂球进行了性别诊断,获雄性胚46枚,雌性胚62枚,移植后分别获雄性仔鼠4只,准确率100％（4／4）,雌性仔鼠9只,准确率70％（9／13）,本研究结果表明小鼠Y染色体重复序列145C5的碱基顺序在C57BL6小鼠和昆明白小鼠中基本一致,为农牧业动物进行性别选择和运用PCR进行单基因病植入前遗传学诊断提供了方法学基础。     

绵羊胚胎附植分子调控研究进展

胚胎附植是哺乳动物复杂的生殖生理过程,是妊娠建立的标志和首要环节。早期胚胎发育、母体妊娠识别、胚胎附植和妊娠维持都严格依赖于孕体和中间的信号联系。大量研究证明,在绵羊胚胎附植过程中,来源于胚胎、母体子宫及宫外组织的多种生殖激素、黏附分子、细胞外基质、细胞活素物质和生长因子通过极其精密的协调共同参与和维持了孕体的发育、子宫内膜的重塑、分泌功能和子宫生长。综述了近年来绵羊胚胎附植的相关分子调控机制的最新研究进展,对胚胎附植分子调控信号的掌握将有助于诊断和确定那些引起妊娠失败的原因,为提高家畜和人类妊娠率提供参考。     

MicroRNA expression and regulation in mouse uterus during embryo implantation

MicroRNAs (miRNAs) are 21-24-nucleotide non-coding RNAs found in diverse organisms. Although hundreds of miRNAs have been cloned or predicted, only very few miRNAs have been functionally characterized. Embryo implantation is a crucial step in mammalian reproduction. Many genes have been shown to be significantly changed in mouse uterus during embryo implantation. However, miRNA expression profiles in the mouse uterus between implantation sites and inter-implantation sites are still unknown. In this study, miRNA microarray was used to examine differential expression of miRNAs in the mouse uterus between implantation sites and inter-implantation sites. Compared with inter-implantation sites, there were 8 up-regulated miR-NAs at implantation sites, which were confirmed by both Northern blot and in situ hybridization. miR-21 was highly expressed in the subluminal stromal cells at implantation sites on day 5 of pregnancy. Because miR-21 was not detected in mouse uterus during pseudopregnancy and under delayed implantation, miR-21 expression at implantation sites was regulated by active blastocysts. Furthermore, we showed that Reck was the target gene of miR-21. Our data suggest that miR-21 may play a key role during embryo implantation.     

胚胎着床过程中血管生成相关因子的表达及其调控

血管生成（angiogenesis）主要在雌性生殖器官中发生,在其它器官和组织中则很少见。许多血管生成相关因子参与血管生成。在哺乳动物的胚胎着床过程中,胚胎着床位点处子宫内膜的血管通透性发生变化,随后进行蜕膜化及胎盘形成,以利于胎儿进一步发育,这些过程均与血管生成相关。本文综述了近年来关于血管内皮生长因子等血管生成因子在着床过程中的表达、调节以及作用机制。     

GRP78 expression and regulation in the mouse uterus during embryo implantation

The aim of this study was to investigate the spatiotemporal expression and regulation of GRP78 in the mouse uterus during the peri-implantation period. The GRP78 protein was mainly detected in the luminal and glandular epithelia on days 1–4 of pregnancy. On day 5 of pregnancy, the GRP78 protein was more highly observed around the implanted embryo at the implantation site. There was no detectable GRP78 protein signal on day 5 of pseudopregnancy. GRP78 mRNA and protein levels gradually increased on days 6–8 of pregnancy, and the expression pattern was also expanded, coinciding with the development of decidua. Similarly, GRP78 expression was also strongly expressed in decidualised cells following artificial decidualisation. Compared with the results obtained with the delayed uterus, a high level of GRP78 expression was detected in the implantation-activated uterus. In the uteri of ovariectomised mice, GRP78 expression increased and reached its highest level after injection of oestrogen, and progesterone seemed to have an antagonistic effect on oestrogen up-regulation of GRP78 expression. Our data indicate that GRP78 might play an important role during the process of mouse embryo implantation, and GRP78 expression was mainly regulated by active blastocysts and maternal oestrogen.     

Navigating the site for embryo implantation: Biomechanical and molecular regulation of intrauterine embryo distribution

The distribution of intrauterine embryo implantation site(s) in most mammalian species shows remarkably constant patterns: in monotocous species such as humans, an embryo tends to implant in the uterine fundus; in polytocous species such as rodents, embryos implant evenly along the uterine horns. These long-time evolved patterns bear great biological significance because disruption of these patterns can have adverse effects on pregnancies. However, lack of suitable models and in vivo monitoring techniques has impeded the progress in understanding the mechanisms of intrauterine embryo distribution. These obstacles are being overcome by genetically engineered mouse models and newly developed high-resolution ultrasound. It has been revealed that intrauterine embryo distribution involves multiple events including uterine sensing of an embryo, fine-tuned uterine peristaltic movements, time-controlled uterine fluid reabsorption and uterine luminal closure, as well as embryo orientation. Diverse molecular factors, such as steroid hormone signaling, lipid signaling, adrenergic signaling, developmental genes, ion/water channels, and potentially embryonic signaling are actively involved in intrauterine embryo distribution. This review covers the biomechanical and molecular aspects of intrauterine embryo distribution (embryo spacing at the longitudinal axis and embryo orientation at the vertical axis), as well as its pathophysiological roles in human reproductive medicine. Future progress requires multi-disciplinary research efforts that will integrate in vivo animal models, clinical cases, physiologically relevant in vitro models, and biomechanical/computational modeling. Understanding the mechanisms for intrauterine embryo distribution could potentially lead to development of therapeutics for treating related conditions in reproductive medicine.     

Differential regulation of endocannabinoid synthesis and degradation in the uterus during embryo implantation

Preimplantation embryo development to the blastocyst stage and uterine differentiation to the receptive state are prerequisites for embryo implantation. Burgeoning evidence suggests that endocannabinoid signaling is critical to early pregnancy events. Anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoylglycerol) are two major endocannabinoids that bind to and activate G-protein coupled cannabinoid receptors CB1 and CB2. We have previously shown that a physiological tone of anandamide is critical to preimplantation events in mice, since either silencing or amplification of anandamide signaling causes retarded development and oviductal retention of embryos via CB1, leading to deferred implantation and compromised pregnancy outcome. Whether 2-AG, which also influences many biological functions, has any effects on early pregnancy remains unknown. Furthermore, mechanisms by which differential uterine endocannabinoid gradients are established under changing pregnancy state is not clearly understood. We show here that 2-AG is present at levels one order of magnitude higher than those of anandamide in the mouse uterus, but with similar patterns as anandamide, i.e. lower levels at implantation sites and higher at interimplantation sites. We also provide evidence that region- and stage-specific uterine expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), and sn-1-diacylglycerol (DAG) lipase alpha (DAGLalpha) and monoacylglycerol lipase (MAGL) for synthesis and hydrolysis of anandamide and 2-AG, respectively, creates endocannabinoid gradients conducive to implantation. Our genetic evidence suggests that FAAH is the major degrading enzyme for anandamide, whereas COX-2, MAGL and to some extent COX-1 participate in metabolizing 2-AG in the pregnant uterus. The results suggest that aberrant functioning of these pathways impacting uterine anandamide and/or 2-AG levels would compromise pregnancy outcome.     

胚胎植入中白细胞介素-1的信号转导及其生理作用

本文论述了白细胞介素－１（ＩＬ－１）的信号转导通路及其在胚胎植入中的调节作用。指出：植入过程中,ＩＬ－１起着十分重要的作用,但并非唯一的重要因子,成功的胚胎植入需要多种细胞因子的协同作用。     

Involvement of microRNA lethal-7a in the regulation of embryo implantation in mice

MicroRNAs interact with multiple mRNAs resulting in their degradation and/or translational repression. This report used the delayed implantation model to determine the role of miRNAs in blastocysts. Dormant blastocysts in delayed implanting mice were activated by estradiol. Differential expression of 45 out of 238 miRNAs examined was found between the dormant and the activated blastocysts. Five of the nine members of the microRNA lethal-7 (let-7) family were down-regulated after activation. Human blastocysts also had a low expression of let-7 family. Forced-expression of a family member, let-7a in mouse blastocysts decreased the number of implantation sites (let-7a: 1.1±0.4; control: 3.8±0.4) in vivo, and reduced the percentages of blastocyst that attached (let-7a: 42.0±8.3%; control: 79.0±5.1%) and spreaded (let-7a: 33.5±2.9%; control: 67.3±3.8%) on fibronectin in vitro. Integrin-β3, a known implantation-related molecule, was demonstrated to be a target of let-7a by 3'-untranslated region reporter assay in cervical cancer cells HeLa, and Western blotting in mouse blastocysts. The inhibitory effect of forced-expression of let-7a on blastocyst attachment and outgrowth was partially nullified in vitro and in vivo by forced-expression of integrin-β3. This study provides the first direct evidence that let-7a is involved in regulating the implantation process partly via modulation of the expression of integrin-β3.     

Lipid signaling in embryo implantation

A reciprocal interaction between the implantation-competent blastocyst and the receptive uterus is required for successful implantation. Although various molecular pathways are known to participate in this cross-talk, a comprehensive understanding of the implantation process is still missing. Gene expression studies and genetically engineered mouse models have provided evidence that lipid mediators serve as important signaling molecules in coordinating the series of events during early pregnancy including preimplantation embryo formation and development, implantation and postimplantation growth. This review focuses on the roles of two groups of lipid mediators, prostaglandins (PGs) and endocannabinoids, during early pregnancy. Our laboratory has shown that while PGs generated by the cPLA2-cyclooxygenase (COX) system are essential to ovulation, fertilization, and implantation, endocannabinoids are important for synchronizing preimplantation embryo development with uterine receptivity for implantation. A better understanding of these molecular signaling pathways is hoped to generate new strategies to correct implantation failure and improve pregnancy rates in women.