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. 2023 Sep 28;48(9):1377–1387. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.220485

非编码RNA在胚胎着床中作用的研究进展

Research progress in the role of non-coding RNAs and embryo implantation

LIU Lin 1,2, GUO Jiayi 2, GAO Wenxin 1, GAO Mengmeng 3, MA Xiaoling 1,✉
Editors: 宋 柳, 郭 征
PMCID: PMC10929864  PMID: 38044649

Abstract

Non-coding RNA (ncRNA) refers to RNA that lack the ability to encode protein. Based on their distinct biological characteristics, ncRNA are mainly classified into microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). NcRNA plays a crucial regulatory role in various biological processes. Pregnancy is a highly intricate physiological process that requires successful completion of multiple steps. Embryo implantation, as a key event of pregnancy, which is regulated by numerous factors, including embryo development, endometrial changes, and the maternal-embryo crosstalk. A diverse array of regulatory mechanisms ensures the accomplishment of embryo localization, adhesion, invasion, and ultimately successful implantation. MiRNA, lncRNA, and circRNA are extensively studied ncRNA molecules at present, which play an important role in the physiological and pathological processes associated with embryo implantation through targeting and regulating the expression of multiple cytokine and genes. With advancements in molecular biology technology, it is anticipated that ncRNA will contribute to the prediction and enhancement of clinical pregnancy outcomes from a molecular perspective.

Keywords: non-coding RNA, embryo implantation, endometrial receptivity, maternal-embryo crosstalk

人类的成功妊娠取决于一系列事件，包括子宫内膜蜕膜化、胚胎着床、胎盘形成和分娩，前一阶段的顺利进行是进入下一阶段的保障[1]。良好的胚胎着床需要具备着床能力的胚泡、接受性的子宫内膜以及二者之间密切的相互作用，即进行母体-胚胎(以下简称“母-胎”)“通信”[2]。对于人类而言，母-胎“通信”自胚胎从透明带中孵化出来开始，在子宫内持续至妊娠结束，“通信”的存在使得子宫腔内能够形成有利于胚胎着床的微环境。

子宫内膜组织仅在短暂的时间内表现为接受性，允许胚胎的定位、黏附、侵入，这段关键时期即为“种植窗”(window of implantation，WOI)，相当于女性月经周期(28 d)的第20~24天或排卵后的第6~8天，持续约48 h。在此期间，人体内构建起的子宫内膜容受性涉及子宫内膜上皮细胞(endometrial epithelial cells，EECs)分泌黏附分子、子宫内膜基质细胞(endometrial stromal cells，ESCs)发生蜕膜化、内膜血管重塑等一系列复杂的改变，其中，蜕膜化是后续胚胎着床及维持妊娠的关键步骤。蜕膜化期间，ESCs转变为具有分泌功能的蜕膜细胞，使得内膜能够为胚胎发育和胎盘形成提供最佳环境。此外，为保证妊娠的顺利进行，蜕膜组织中浸润的白细胞介导母体对胚胎来源的同种异体抗原做出应答，在体内建立起母-胎免疫耐受，这一过程是妊娠成功的必备条件[3]。在蜕膜化过程中，随着胚胎滋养层不断侵入子宫内膜，胎盘开始发育，并逐渐形成独立的母-胎血液循环。因此，胚胎着床的顺利进行对成功的妊娠具有重要意义，研究胚胎着床的调控机制十分重要。

非编码RNA(non-coding RNA，ncRNA)指不具备编码蛋白质潜力的RNA。虽然ncRNA在过去被认为是“进化垃圾”，但近年来许多研究发现ncRNA在心血管系统[4]、神经系统[5]、生殖系统[6-7]等中均参与调控基因表达的过程。同时，随着竞争性内源RNA(competing endogenous RNA，ceRNA)网络假说的提出，包括长链非编码RNA(long non-coding RNA，lncRNA)、环状RNA(circular RNA，circRNA)在内的多种RNA均可通过竞争性结合微RNA(microRNA，miRNA)在多种生命活动中发挥重要的调控作用。

本文就miRNA、lncRNA及circRNA在胚胎着床中发挥调控作用的研究进展进行综述(图1)，从分子调控角度为临床上改善妊娠结局提供可能的思路和方法。

图1.

图1

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非编码RNA在胚胎着床中的调控作用

Figure 1 Regulatory role of non-coding RNA (ncRNA) in embryo implantation

Process of mammalian embryo implantation involves the sequential development of a fertilized egg into morula, blastocyst, and other stages. Simultaneously, the maternal endometrium undergoes decidualization and various changes to establish endometrial receptivity. Additionally, there is frequent and intricate “crosstalk” between the mother and embryo. NcRNA plays a crucial regulatory role in this process. This figure was drawed by figdraw (https://www.figdraw.com). C19MC: Chromosome 19 miRNA cluster; ESCs: Endometrial stromal cells; lncRNA: Long non-coding RNA.

1. MiRNA

MiRNA是一类长度约为20 nt的ncRNA[8]，在动物、植物、病毒中发挥重要的基因调控作用。多种miRNA不同程度地参与了哺乳动物的胚胎着床、早期发育、胚层及性别分化、妊娠维持等繁殖过程[9]。

1.1. 胚胎来源的miRNA调节胚胎发育

胚胎发育受到一些胚胎来源miRNA的影响，它们可能通过调节胚胎细胞的增殖分化及胚胎状态进而调控胚胎着床。研究[10]表明：牛胚胎miRNA在胚胎基因组激活、桑葚胚期、囊胚期均存在广泛的调控作用，且囊胚期特异性表达的miRNA在调控干细胞分化的通路中显著富集。MiRNA的调控作用为理解囊胚分化的具体机制提供了方向。在小鼠胚胎中miR-124a通过下调SRY-box转录因子17(SRY-related HMG-box 17，Sox17)和GATA结合蛋白6(GATA binding protein 6，GATA6)抑制内胚层的发育[11]。19号染色体的miRNA簇(chromosome 19 miRNA cluster，C19MC)参与调节胚胎干细胞多能性的转化，在人类滋养层干细胞增殖和分化中发挥重要的调控作用[12]。

1.2. 母体来源的miRNA调节子宫内膜状态

MiRNAs表达水平的变化与子宫内膜状态的改变息息相关。胚胎着床发生于卵巢的黄体期中期，此时处于分泌期的子宫内膜在多种因素的调控下建立起子宫内膜容受性。分泌期前后的子宫内膜中miRNA表达谱会发生动态变化，提示miRNA参与内膜状态的调节[13]。正常生育女性的子宫内膜中有91个miRNA在分泌期早期和分泌期中期差异表达，其中miR-30家族和miR-200家族通过影响的细胞增殖、迁移等途径调控子宫内膜容受性的建立[14]。在一项细胞培养实验[15]中，孕激素的刺激使一些miRNA (miR-340-5p、miR-542-3p和miR-671-5p)在ESCs中的表达上调，其蛋白质靶点参与调节子宫内膜蜕膜化和容受性的建立。

1.3. MiRNA在母-胎“通信”中影响胚胎着床

胚泡进入子宫之初，在一组趋化因子和黏附因子[如白血病抑制因子(leukaemia inhibitory factor，LIF)、整合素、L-选择素等]的作用下，滋养层细胞定位并黏附EECs。小鼠子宫内膜中的Emx2-miR-181轴能够直接靶向并下调LIF的表达，可能会抑制胚胎着床的状态[16]。

随后，胚胎的滋养层细胞侵入内膜基质，内膜发生蜕膜化。一项细胞培养实验[17]表明：在人子宫内膜基质细胞(human endometrial stromal cells，hESCs)中过表达miR-542-3p抑制了整合素连接激酶(integrin-linked kinase，ILK)及下游转化生长因子-β1(transforming growth factor-β1，TGF-β1)、Smad2的表达，进而抑制hESCs增殖、侵袭、凋亡，同时下调环氧合酶2(cyclooxygenase-2，Cox-2)、血管内皮生长因子(vascular endothelial growth factor，VEGF)等血管生成因子，阻碍体外模拟蜕膜化期间的血管生成；在大鼠ESCs中过表达miR-145会引发相似的效应[18]，影响蜕膜化。在蜕膜白细胞介导下建立的母-胎免疫耐受，是妊娠成功的必备条件。蜕膜白细胞主要由自然杀伤(natural killer，NK)细胞组成，它与母体免疫耐受的关系最为密切。蜕膜NK细胞与外周血NK细胞的miRNA表达谱并不相同，且某些差异性表达的miRNA可能介导了炎症性生殖系统疾病的发生，关系到妊娠是否能够维持[19]。蜕膜NK细胞中多种miRNA差异性表达可能与不明原因复发性流产有关[20]。蜕膜白细胞中还包括巨噬细胞、T细胞，miR-31能够靶向抑制叉头框蛋白P3(forkhead box P3，FOXP3)、趋化因子CXC配体12(C-X-C motif chemokine ligand 12，CXCL12)的表达，介导巨噬细胞、CD4+调节性T细胞建立免疫耐受[21]。伴随着蜕膜化的进程，胎盘开始发育，大量由C19MC表达的miRNA参与其中，如miR-675[22]。

在母-胎“通信”过程中，存在一种可以穿越细胞间、细胞-环境间生理屏障的“通信”方式——细胞外囊泡(extracellular vesicles，EVs)。它能够携带特定的ncRNA参与母-胎“通信”，其中主要是miRNA(如miR-100-5p)[23]。WOI期间的子宫内膜细胞释放更多的EVs以支持胚胎着床[23]。此外，EVs的媒介作用广泛存在于子宫腔液、胚胎滋养层细胞[24]，精液、卵泡液中也分离出EVs[25]。胞外体是EVs的一种特殊类型，胚胎和子宫内膜来源的胞外体中存在多种miRNA，它们可能通过母-胎“通信”影响胚胎着床及母体的免疫耐受、妊娠维持[26]。EVs这一独特的“通信”方式可能成为评估子宫内膜状态及胚胎质量的非侵入性液体活体组织检查工具，帮助改善生殖过程；同时，随着分离纯化技术的进步及靶向性的提升，EVs将有可能成为良好的药物载体。

当特定miRNA的表达发生改变时可能会影响胚胎发育、子宫内膜状态并扰乱母-胎“通信”，导致异常的胚胎着床。例如，miR-21在多囊卵巢综合征患者的卵泡液中表达升高，可能阻碍卵丘扩张、卵母细胞成熟及胚胎发育，导致卵泡功能障碍且不利于胚胎着床[27]。其他影响着床的疾病如子宫内膜异位症发病被证实与miR-135a/b有关[28]。与正常ESCs相比，因子宫内膜异位症导致不孕的患者ESCs分泌的胞外体差异性表达49个miRNA，这些miRNA可能参与调控丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)和Wnt信号通路，干扰子宫内膜容受性[29]。

MiRNA的调控作用对于顺利着床具有重要意义，其在正常、异常胚胎着床过程中的部分调控作用分别见表1 [18, 30-39]、2[40-51]。

表1.

与正常胚胎着床相关的miRNA

Table 1 MiRNA associated with normal embryo implantation

MiRNA 表达水平 参与正常胚胎着床的潜在机制 研究对象 参考文献
miR-145 ↓ 通过靶向Smad1/5/8、Wnt-4、MMP-9、Cox-2和VEGF，调节蜕膜化 大鼠 [18]
miR-15b ↑

LncRNA-882与TAB3竞争结合此miRNA，间接调控奶

山羊EECs中LIF的表达水平，调节子宫内膜容受性

 奶山羊 [30]
miR-98 ↓ 经EVs介导调节母体免疫系统，调节胚胎与子宫内膜间的黏附作用 牛 [31]

miR-21；miR-451；

miR-204；miR-199a-5p；

miR-199b-5p

 — 妊娠第12天差异性表达miRNA，通过p53信号通路和Wnt信号通路在胚胎着床中发挥作用 猪 [32]
miR-30a-3p ↓ 通过靶向Snai2，发挥EMT抑制因子的作用，调节胚胎着床 小鼠 [33]
miR-290b-5p ↓ 通过上调NDRG3表达调节蜕膜化 小鼠 [34]
miR-183-5p ↑

抑制EECs中CTNNA2表达，并在雌激素介导下提高

子宫内膜容受性

 人；小鼠 [35]
miR-let-7a/g ↑ 抑制Wnt信号转导，并在卵巢激素的调节下，提高子宫内膜容受性 人 [36]
miR-let-7f-5p；miR-let-7g-5p ↑ 通过抑制IGF2BP-1和IGF2R的表达调节蜕膜化 人 [37]
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表2.

与异常胚胎着床相关的miRNA

Table 2 MiRNA associated with abnormal embryo implantation

MiRNA 表达水平 参与正常胚胎着床的潜在机制 研究对象 参考文献
miR-lin28a ↑

在Wnt/β-catenin信号转导调控下表达上调，促进胚胎的

着床能力

 人 [38]
miR-181b-5p ↓ 通过上调TIMP-3、ANXA2的表达促进细胞迁移、黏附，调节蜕膜化 人 [39]
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“↑”表示miRNA表达上调；“↓”表示miRNA表达下调；“—”表示miRNA表达水平在不同时期存在差异。MMP：基质金属蛋白酶；Cox-2：环氧合酶2；VEGF：血管内皮生长因子；TAB3：转化生长因子β活化激酶1结合蛋白3；EECs：子宫内膜上皮细胞；EVs：细胞外囊泡；LIF：白血病抑制因子；Snai2：锌指转录因子2；EMT：上皮-间充质转化；NDRG3：N-myc下游调节基因3；CTNNA2：连环蛋白α；IGF2BP-1：胰岛素样生长因子2-mRNA结合蛋白1；IGF2R：胰岛素样生长因子2受体；TIMP-3：金属蛋白酶组织抑制剂-3；ANXA2：膜联蛋白A2。

表2.

与异常胚胎着床相关的miRNA

Table 2 MiRNA associated with abnormal embryo implantation

MiRNA 表达水平 参与异常胚胎着床的潜在机制 研究对象 参考文献
miR-661 ↑ 通过下调MDM2的表达削弱EECs的胚胎黏附能力，妨碍胚胎着床 人 [40]
miR-320bTT ↑ 在IVF周期中影响胚胎着床，导致着床失败 人 [41]
miR-22-5p ↓ 在黄体中期子宫内膜中表达失衡，导致极轻度/轻度EMs患者不孕 人 [42]
miR-543 ↓ 与子宫内膜容受性的调节有关，参与EMs的发生和发展 人 [43]
miR-200c ↓

通过抑制CD44上的FUT4和α 1.3-岩藻糖基化，

降低子宫内膜容受性，参与不孕和流产的发生和发展

人；

小鼠

 [44]
miR-30d ↓

1)抑制子宫内膜中LIF的表达，导致母体胚胎植入部位较小，胚胎吸收率较高，影响胚胎着床；

2)导致胎仔的头臀长度和胎仔/胎盘重量比较小，影响胚胎发育

 小鼠 [45-46]
miR-184 ↑ 通过靶向WIG1，上调Fas的表达，促进滋养层细胞的凋亡，促进早期流产的发生

人；

小鼠

 [47]
miR-940 ↑

通过下调ZNF672的表达抑制滋养层细胞增殖，

促进早期流产的发生

 人 [48]
miR-378a-3p ↓ 上调Caspase-3的表达导致蜕膜细胞凋亡，促进早期流产的发生和发展 人 [49]
miR-449b；miR-146a/miR-196a2 ↑ 这些miRNA的多态性与RIF的发生和发展有关 人 [50-51]
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“↑”表示miRNA表达上调；“↓”表示miRNA表达下调。MDM2：鼠双微染色体2；EECs：子宫内膜上皮细胞；IVF：体外受精；EMs：子宫内膜异位症；FUT4：岩藻糖基转移酶4；LIF：白血病抑制因子；WIG1：野生型p53诱导基因1；ZNF672：锌指蛋白672；Caspase-3：半胱氨酸蛋白酶-3；RIF：反复着床失败。

1.4. MiRNA的临床转化

MiRNA是一种极具潜力的诊断和预后的生物标志物，胚胎分泌的miRNA可能对评估人类辅助生殖技术(assisted reproductive technology，ART)周期中胚胎质量有指导意义[52]，最佳胚胎着床时间可通过分析子宫内膜表达的miRNA来确定[53]，这将为反复着床失败(repeated implantation failure，RIF)患者争取更多的妊娠可能性。已有研究[54]通过对比RIF患者与非RIF不孕症患者的子宫内膜miRNA表达谱并设计芯片筛选出了3个miRNA，它们在预测RIF时的准确率大于90%。此外，单个miRNA即可通过与靶基因间广泛的相互作用来调控整体细胞通路，这一特性使得miRNA有可能成为功能强大的基因治疗工具，多种载体、化学修饰策略的应用进一步提升了miRNA给药治疗的靶向性。有研究[55]设计了一种胞外体胶原蛋白支架(exosomes and collagen scaffold，CS/Exos)，发现子宫内膜来源胞外体中富集的miRNA可能凭借其免疫调节功能抑制炎症因子如白细胞介素(interleukin，IL)-1β等的表达并增强抗炎作用，且支架的移植能够促进子宫内膜再生，有助于改善子宫腔粘连(intrauterine adhesion，IUA)患者的不孕症状。

2. LncRNA

LncRNA是一类长度大于200 nt的ncRNA，与miRNA相比，lncRNA因其在进化保守性、表达水平及分子功能等方面的特点引起了学界的关注[8]。然而，绝大多数lncRNA的功能仍未被揭示。随着RNA测序等技术的应用及ceRNA网络假说的提出，人们开始更全面、深入地理解lncRNA在多种生物学过程中的作用机制。

2.1. 胚胎来源的lncRNA调节胚胎发育

研究[56]表明：在哺乳动物的早期胚胎(由受精卵发育至囊胚阶段)中能够检测到丰富的lncRNA，且各时期的lncRNA表达谱明显不同，猪胚胎在卵母细胞期至2细胞期期间几乎无lncRNA表达，但其在4细胞期至囊胚期期间lncRNA高表达，并与调控胚胎DNA甲基化、多能性基因、细胞凋亡等行为的基因同步活化，从而调节胚胎发育。对于哺乳动物的雌性胚胎，胚胎父系X染色体表达的X-非活性特异性转录物(X iactive specific transcript，Xist)lncRNA会与多种蛋白质发生相互作用，最终使该染色体的转录沉默，Xist lncRNA的缺失将导致胚胎的全基因组转录调控错误，且不能激活滋养层细胞、胎盘等胚胎外组织发育所必需的基因，最终导致胚胎失活、着床失败[57]。

2.2. 母体来源的lncRNA调节子宫内膜状态

与胚胎发育的调节类似，大量lncRNA参与构建子宫内膜容受性，且其表达具有阶段特异性。运用RNA测序技术在奶山羊容受期前后的子宫内膜组织中检测到668个差异表达的lncRNA，其中lncRNA-882与miR-15b的ceRNA共同调节奶山羊子宫内膜上皮细胞(dairy goat endometrial epithelial cells，gEECs)中LIF的表达水平，协助子宫内膜容受性的构建[30]。有研究[58]在育龄妇女的增殖期、分泌中期内膜中共鉴定出247个差异表达的lncRNA，且提出3条ceRNA轴(lncRNA dlx6-AS1/miR-141或miR-200a/OLFM1轴、lncRNAWDFY3-AS2/miR-135a或miR-183/STC1轴、lncRNA-00240/miR-182/NDRG1轴)可能参与了子宫内膜容受性的调节。

2.3. LncRNA在母-胚“通信”中影响胚胎着床

研究[59]表明：一方面，胚胎滋养层细胞中lncRNAH19/miR-let-7/ITGB3轴可以调节胚胎的黏附、侵袭能力；另一方面，受囊胚分泌的某些因子的刺激，EECs通过lncRNA PTENP1/miR-590-3p/PTEN轴作出回应，从而调控胚胎的黏附。还有研究[60]提出胚胎黏附、蜕膜化等过程可能受到内膜表达的lncRNA TUNAR的调节。

2.4. LncRNA与异常胚胎着床

研究[61]发现：通过抑制子宫内膜增殖构建胚胎植入功能障碍的小鼠，小鼠子宫内膜lncRNA NEAT1表达增加并抑制HOXA10与转录因子的结合，阻碍子宫内膜增殖及建立容受性。一项生物信息学分析[62]结果显示：与子宫内膜异位症、RIF患者的内膜相比，某些lncRNA(ENST00000414116、ENST00000433673、ENST00000448179)在正常内膜组织中表达上调，经预测，lncRNA ENST00000433673可能靶向整合素从而调节胚胎的黏附。LncRNAC01279/miR-135b/HOXA10网络参与调节ESCs的异常增殖及迁移，并进一步导致EMs的发生和发展[63]。

2.5. LncRNA的临床转化

有研究[64]筛选出了8个用于预测RIF的lncRNA(LINC00645、LINC00844、LINC02349、AC010975.1、AC022034.1、AC096719.1、AC104072.1、DLGAP1-AS3)，并进一步提出其中AC096719.1和AC104072.1可用于确定RIF的发生和发展中是否存在子宫内膜因素，这在将来可以用于real-time PCR诊断以预测接受体外受精-胚胎移植的妇女成功妊娠的概率。

3. CircRNA

CircRNA是一类通过反向剪接形成的封闭的环状结构ncRNA，它不具有5'-帽端和3'-尾端，普遍存在于人类基因组转录物中。CircRNA在转录后基因调控中发挥重要作用，可以作为miRNA“海绵”或通过直接干扰mRNA前体的选择性剪切等方式调控基因表达[8]。近年有研究[65]突破性地提出某些circRNA能够编码小分子蛋白质进而参与基因调控。CircRNA多样化的生物学功能在一些人类疾病中已经得到了研究，而生殖系统中circRNA的作用还有待进一步探索。

3.1. 胚胎来源的circRNA调节胚胎发育

一项小鼠早期胚胎(受精卵至囊胚阶段)单细胞RNA测序研究[66]显示：circRNA的数量在胚胎4~8细胞期达到顶峰，基因本体(Gene Ontology，GO)分析表明这一期间表达的circRNA可能与胚胎染色体的结构、细胞周期的调节及损伤DNA的修复有关。兔胚胎的全基因组测序结果[67]提示circRNA可能通过Wnt、磷脂酰肌醇-3-激酶/蛋白激酶B (phosphoinositide-3-kinase/protein kinase B，PI3K/Akt)等信号通路调控胚胎发育。还有研究[68]发现，circKDM5B作为miR-128的ceRNA，敲减其表达将导致胚胎移植后囊胚数量的明显减少及滋养外胚层发育受阻。此外，相较于母系线性RNA的降解趋势，circRNA在小鼠卵母细胞向合子转变的过程中更加稳定[66]，这提示我们circRNA独特的生物学特性可能有利于它在更多的生命活动中发挥调控作用。

3.2. 母体来源的circRNA调节子宫内膜状态

有研究[69]对是否处于容受期(day 16)的子宫内膜进行高通量RNA测序分析，鉴定出18个差异性表达的circRNA，这些分子可能作为55个miRNA的“海绵”起调控作用，通过MAPK、TGF-β等信号通路调节gEECs的增殖、凋亡，参与子宫内膜容受性的构建。此外，ciR-8073/miR-181a/NT及ciR-9119/miR-26a/PTGS2通路参与调节奶山羊子宫内膜容受性[70-71]。

3.3. CircRNA在母-胎“通信”中影响胚胎着床

及circRNA与异常胚胎着床

早孕小鼠(day 5)胚胎着床点间和着床点处内膜组织的不同分化行为以及胚胎黏附的调节可能与多条circRNA/miRNA/mRNA通路有关[72]。滋养层细胞的迁移、侵袭异常可能与hsa_circ_0000848及ciR-ZUFSP/miR-203/STOX1相关，它们分别参与调控了胎儿生长受限及反复自然流产的病理进程，hsa_circ_0000848还可作为hsa-miR-6768-5p的“海绵”，调控细胞凋亡[73-74]。母-胎构建免疫耐受的过程可能受到hsa-MORC3_0001/hsa-miR-1248/CHRM2等多条通路的调节，由此产生的免疫功能失调介导了宫腔内的炎症反应并导致早产[75]。此外，本研究组前期成果[76]表明RIF患者的子宫内膜与正常患者相比有856个circRNA的表达失调，并确认了circRNA-070616、circRNA-103716、circRNA-0001550、circRNA-104854表达上调，circRNA-004183、circRNA-044353、circRNA-404686表达下调。进一步的研究[77]发现，circRNA-0001550的表达增加抑制hESCs的增殖和细胞的活力，促进细胞凋亡，阻碍蜕膜化进程及正常胚胎着床。由3个circRNA(circ-0058161、circ-0033392、circ-0030162)和4个靶基因(YWHAZ、JAK2、MYH9、RAP2C)构成的调控网络及circRNA-0038383/miR-196b-5p/HOXA9、hsa_circ_001946/miR-135b/HOXA10通路可能也参与了RIF的发生和发展[78-80]。最近的一项研究[81]表明，在人脐带来源的间充质干细胞(Wharton’s jelly-derived mesenchymal stem cells，WJ-MSCs)诱导的受损子宫内膜修复过程中，血管的生成与ciR-6401/miR-29b-1-5p/rap1b通路有关。这提示我们，WJ-MSCs通过ncRNA发挥的治疗性血管生成及组织修复功能或许可以为某些胚胎着床异常患者的治疗提供新思路，ciR-6401可作为潜在的治疗靶点。

4. 结 语

NcRNA在胚胎着床过程中的重要调控作用体现在胚胎发育、子宫内膜状态的调节等多方面，它们的异常表达与多种疾病的发生和发展相关，如RIF、EMs等。近年来，随着以ceRNA网络为基础的分子调控通路研究的不断深入及提取、设计EVs技术的进展，一些研究成果正在向临床转化，ncRNA作为筛查、诊断、治疗及预后的生物标志物的潜力逐渐凸显。尽管越来越多的研究证实，在胚胎着床过程中ncRNA是潜在的生物标志物和基因治疗工具，但这些ncRNA如何独自或者联合调控胚胎着床的机制以及它们的作用如何向临床转化，仍需要进一步深入挖掘。此外，一些研究中的大样本预测和筛选结果仍需进一步的验证。这些问题的探索将有助于今后临床中改善妊娠失败患者的诊断和治疗。

基金资助

国家自然科学基金(81960279，82360307)；兰州市人才创新创业项目(2022-RC-47)；兰州大学医学科研创新能力提升项目(lzuyxcx-2022-191)。

This work was supported by the National Natural Science Foundation (81960279, 82360307), the Lanzhou Talents Innovation and Entrepreneurship Project (2022-RC-47), and the Lanzhou University Medical Research Innovation Ability Promotion Project (lzuyxcx-2022-191), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

刘琳 论文审阅、修订；郭佳仪 文献收集及论文撰写；高文欣、高萌萌 文献收集、总结；马晓玲 论文审阅、指导。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023091377.pdf

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