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通讯作者:

李蓉(1974-),女,北京人,博士生导师,主要从事女性生育力的评估、保护及子宫内膜容受性的研究。E-mail:roseli001@sina.com

中图分类号:R321.3

文献标识码:A

文章编号:2096-8965(2022)04-0058-07

DOI:10.12287/j.issn.2096-8965.20220408

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目录contents

    摘要

    子宫内膜容受性是胚胎成功着床的关键,其异常是胚胎着床失败及不孕的主要原因,而传统的子宫内膜形态学观察方法无法充分确定子宫内膜容受性的状态。近年来,多组学技术的发展为生理病理条件下的子宫内膜功能特征研究提供了便捷有效的分析方法。因此,本文对转录组学、蛋白质组学及代谢组学等在人类子宫内膜容受性相关研究中的应用进行综述,旨在深入了解子宫内膜容受性并发掘新技术以强化子宫内膜植入窗口期检测的准确性,从而提高辅助生殖技术周期中怀孕的几率。

    Abstract

    Endometrial receptivity is critical for successful embryo implantation, and endometrial receptivity abnormalities are major causes of embryo implantation failure and infertility. However, the traditional way cannot be adequately determined the condition of receptivity by morphological observation of endometrium. In recent years, the development of muli-omics technologies provides a convenient and effective analytical approach to study the functional characteristics of the endometrium in physiological and pathological conditions. This paper reviews the application of transcriptomics, proteomics and metabolomics in human endometrial receptivity studies, with the aim of gaining insight into endometrial receptivity and discovering new technologies to enhance the accuracy of endometrial implantation window detection, thereby improving the chances of pregnancy in assisted reproductive technology cycles.

  • 0 前言

  • 胚胎植入是一项复杂的生理过程,胚胎附植的成功需要激活状态的囊胚、处于容受状态的子宫内膜以及二者之间的同步性[1]。子宫内膜允许正常着床的能力称为容受性,该时期持续 12小时到 2天,因人而异[2]。在复杂的生理过程中涉及到多种调节因素,其分子机制尚未完全解析。良好的子宫内膜容受性对于成功的胚胎附植和妊娠至关重要,对女性生育力维持有重要意义。研究显示,子宫容受性降低以及胚胎和子宫内膜之间不同步是不孕症及复发性流产的主要原因,提高子宫内膜容受性可以改善体外受精-胚胎移植的结果[3]。因此,寻找子宫内膜容受性标志物是协助诊治妊娠相关子宫内膜源性疾病亟待解决的问题。

  • 目前,临床评估子宫内膜容受性的方法主要有超声检查、宫腔镜检查和子宫内膜活检,它们只是简单进行子宫内膜形态学观察,不能充分确定容受性状况。因此需要更有效的子宫内膜容受性评估方法。随着生物学技术的发展,组学技术作为一种功能强大的定量定性分析技术,在生理病理研究方面的应用越来越广泛。目前,常用的组学技术包括转录组学、蛋白质组学、代谢组学和单细胞测序等,各组学数据在一定程度上为研究群体、个体、器官、组织、细胞与亚细胞等层面的生物学功能和分子调控途径提供了可靠的数据支持,可更深入地掌握子宫内膜容受性调控的分子机制并提高子宫内膜容受性异常的诊断准确性和可靠性。本文我们将重点对多组学技术在子宫内膜容受性及容受性相关疾病中的诊断以及治疗中的应用现状和进展作一综述。

  • 1 子宫内膜容受性定义及其影响因素

  • 子宫内膜容受性是一个复杂的过程,它为激活状态的囊胚提供附着、侵入和发育的机会,最终形成一个新的个体和物种的延续[4]。植入窗口在狭窄时间范围内,具有最大的子宫内膜容受性,在人类,子宫内膜对胚胎的最大接受期是在排卵后 7-10天[5]。良好的子宫内膜容受性使子宫内膜能够为胚胎发育和胎盘形成提供最佳环境[6]。异常容受性的程度和类型会导致一系列生殖问题,如先兆子痫、流产和不孕等[7]。子宫内膜容受性受损被认为是胚胎植入失败的主要原因。

  • 目前,干扰子宫内膜容受性的因素未被完全解析,但主要有以下几个方面:(1) 母体本身因素:高龄、多囊卵巢、子宫内膜异位症等[8-10];(2) 子宫内膜本身因素:子宫内膜厚度、血流状态等[11]; (3) 宫腔解剖结构异常:女性生殖系统疾病导致的宫腔粘连、子宫内膜息肉、子宫肌瘤等[12]。基于以上原因,当子宫内膜没有处于容受状态时,容易导致胚胎植入失败。因此,子宫内膜容受性评估的正确与否,直接决定了胚胎是否可以正常植入及妊娠结局。

  • 2 多组学分析技术在子宫内膜容受性中的研究进展

  • 2.1 子宫内膜容受性的转录组学分析

  • 转录组学是从 RNA 水平研究不同组织、不同时间基因表达的情况,是研究细胞表型和功能的一个重要手段,包括 mRNA 和非编码 RNA。目前已经成为临床诊断疾病的有力工具。

  • 2.1.1 子宫内膜容受性阵列

  • 子宫内膜容受性阵列 (Endometrial Receptivity Array,ERA) 是 Lgenomix 开发的全球首个诊断女性子宫内膜容受性、并精准预测种植窗的分子检测技术,通过分析子宫内膜容受性功能相关248个基因的表达,从而预测胚胎附植最佳时间,通过调整黄体酮用药时间,在附植最佳时间进行胚胎移植可提高种植成功率[13]。子宫内膜容受性相关的基因检测的目标性,使其避免了全基因组微阵列的使用,降低成本的同时简化数据分析。ERA比组织学测定更准确,是诊断子宫内膜容受状态的可重复方法[14]。然而,作为一种新的基因组工具,ERA检测有其局限性,需要进行子宫内膜活检[15],其侵入性和胚胎移植只能在下一个周期进行限制了 ERA 的临床应用。此外,对于周期不规律的妇女,实际应用具有很大的局限性[16]。由此可知,ERA技术的发展是建立在子宫内膜容受性标志基因准确鉴定的基础之上,具有简化窗口期判断流程的作用,但适宜检材获取不易,这也成为制约 ERA 推广的主要原因。

  • 2.1.2 子宫内膜非编码RNA

  • 随着高通量测序技术的进步,生物过程的调控不仅依赖于mRNA,还依赖于非编码RNA,如微小 RNA (microRNA, miRNA)、长链非编码 RNA (Long non-coding RNA, lncRNA) 和环状 RNA (Circular RNA,circRNA)[17]。研究发现,miRNA 的表达在子宫内膜的周期变化和病理条件下皆有所不同[1819]。也有研究发现,miRNA 通过调节其相对应靶基因的降解和抑制蛋白质的翻译参与子宫内膜容受性的建立和维持[20]。但miRNA的主要问题是靶向位点特异性差,导致研究得出的结论缺乏一致性。研究发现,一系列 lncRNA 在妊娠和非妊娠子宫内膜中的表达量和表达模式不同,提示 lncRNA 在子宫内膜容受性中起重要的作用,但由于目前研究并不深入,得到确切的特异性标记分子有限[21]。circRNA具有极其丰富的miRNA结合位点,因此可以竞争性地结合 miRNA 海绵或与 RNA 结合蛋白相互作用来调节基因表达[22]。综上所述,虽然非编码 RNA 在试验过程中易出现假阳性,但其仍是子宫内膜容受性标志物寻找的主要手段,且随着技术手段的不断革新,非编码 RNA 仍将在后续的研究中发挥着不可或缺的重要作用。目前研究内容及结果总结见表1。

  • 表1 子宫内膜容受性的转录组学研究

  • 2.2 子宫内膜容受性的蛋白质组学分析

  • 蛋白质是大多数生理过程的主要执行者,并且蛋白质组学能够同时检测多种蛋白质,描绘蛋白质谱的整个图谱[44]。研究发现,子宫内膜中发现的蛋白质主要功能与细胞骨架、细胞粘附、蛋白质折叠和信号转导有关。与种植前期相比,种植窗期膜联蛋白 (Annexin) A4的表达较高[45]。另有研究显示, Annexin A2在容受性子宫内膜组织中表达明显比非容受性子宫内膜中高且在子宫内膜基质细胞中高表达,这提示Annexin A2参与蜕膜化过程的调节,并需要肌动蛋白细胞骨架重组[4546]。另有研究发现, Annexin A6 和孕酮膜受体 1 (Progesterone Receptor Membrane Component1,PGRMC1) 是单独的新靶点,并将“碳水化合物生物合成过程”和“通过剪接体进行核mRNA剪接”作为与子宫内膜容受性相关的重要途径[47]。虽然蛋白质组学可以在不同的子宫内膜中发现大量的差异蛋白,但蛋白质的低敏感性及其修饰状态限制了其发展。

  • 2.3 子宫内膜容受性的代谢组学分析

  • 代谢组包括在生物样品中发现的一整套小分子代谢物,也是动态的、响应最轻微的物理或化学信号的变化而变化[48],它包括基因表达的最终下游产物。代谢组提供了有关基因型-表型关系和基因型-环境相互作用的信息[49]。目前,通过组织切片的三维成像技术发现乙酰胆碱信号分子在小鼠怀孕第 6 天蜕膜化中的重要作用[5051]。在接受 IVF 治疗的女性中,确定了子宫内膜前列腺素合成缺陷与反复植入失败之间的关系[5253]。溶血磷脂酸 (Lysophosphatidic Acid,LPA) 是一种水溶性的磷脂,在小鼠中进行的一项研究显示,LPA作为形成正常胚胎的必要条件,是植入的积极因素,通过刺激其受体 LPA3 发挥作用[54]。最近一项研究发现, LPA 通过其受体 LPA3 控制内源性大麻素和前列腺素介质的水平,在接受期调节子宫内膜进行植入[5556]。花生四烯酸乙醇胺 (Anandamide N-arachidonoyl Ethanolamine,AEA) 和 2-花生酰基甘油 (2-arachidonoylglycerol) 在啮齿类动物的附植过程中起着一定的作用,其水平异常导致附植的推迟和妊娠率下降[57]。降解内分泌物的基本酶是脂肪酸酰胺水解酶 (Fatty Acid Amide Hydrolase,FAAH),该酶与体外受精和胚胎移植后的高妊娠率有关[56]。研究显示,FAAH 水平低会导致 AEA 增加,从而使子宫内膜容受性下降[58]。多不饱和脂肪酸可以通过产生前列腺素、雌激素和黄体酮等方式影响子宫内膜容受性,同时多不饱和脂肪酸还参与免疫和子宫内膜蜕膜化的调节[59]。子宫内膜液脂质组学研究似乎是更直接研究脂质代谢与子宫内膜容受性之间关系的理想方法。较其它“组学”而言,脂质组学可能是子宫内膜研究中使用最少的方法。目前的研究始终集中在非靶向脂质组学上,旨在识别脂质生物标志物。而与组织相比,可用于采集的子宫液相对较少,这可能会影响脂质组分析结果,脂质分析从科研走向临床还需要一定的时间。

  • 2.4 子宫内膜与单细胞测序

  • 单细胞是通过特定的技术获得的,由于生物信息技术的发展,可以分析细胞的基因表达、功能和相互作用[60]。子宫内膜组织包括许多不同类型细胞,如腔上皮细胞、腺上皮细胞和基质细胞。 Krjutškov 等[61] 提供了一种新的单细胞转录组方法,通过对新鲜、冷冻和解冻样本的分析,发现该方法专为直接从新鲜组织中的获取的细胞而设计。 Wang 等[62] 通过单细胞转录组分析,将月经周期分为四个主要阶段 (月经及增生早期、增生后期、分泌早期、分泌中后期),并且能够更精确地确定胚胎“着床窗口”。通过单细胞技术对薄型子宫内膜进行研究发现,基质细胞是子宫内膜中最丰富的细胞类型,其细胞周期信号通路在薄型子宫内膜中受损[4761]。另外,Zhang等[63] 发现与对照组相比,薄型子宫内膜组上皮细胞和基质细胞比例差异显著,同时发现差异基因的富集途径与薄型子宫内膜中增殖期和分泌期的蛋白质合成密切相关。传统的测序只能提供整个组织或者细胞群体的特征,掩盖了单个细胞的特征,具有一定的局限性。目前,单细胞测序作为一种新兴的前沿技术,在分析子宫内膜不同细胞间的差异方面具有显著的优势。然而,单细胞测序也有几个局限性:(1) 单细胞 RNA 测序的质量控制过程;(2) 个体存在显著差异,需要通过大样本研究进一步验证;(3) 捕获效率和测序覆盖率低;(4) 成本昂贵和复杂的计算数据分析。单细胞测序在子宫内膜的临床应用虽然受到限制,但随着技术的日新月异,单细胞测序的特殊性有利于进行组织中各类细胞关联分析,将成为后续探索中更为强有力的手段。

  • 3 总结与展望

  • 在精准医疗的大背景下,传统的子宫内膜容受性评估方法已经无法满足临床不孕症治疗的需要,而寻找一种精准有效的评估方式已经迫在眉睫。目前,单一组学广泛应用于子宫内膜容受性的研究中,一些与子宫内膜容受性相关的关键基因、蛋白质和代谢物等相继被挖掘,但这些研究结果仅停留在一维或二维水平,并不能系统地解释子宫内膜容受性复杂的调控过程及机制。而通过多组学研究,结合多种生化手段,从不同生物学通路更加详细地揭示子宫内膜容受性的分子机制。同时,传统方法与多组学技术相融合阐明容受性相关疾病的发病机理,有助于做到靶向治疗和制定个性化诊治方案,从而显著提高怀孕率和活产率,为女性生殖健康开辟新前景。

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