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The role of microRNAs in the regulation of critical genes and signalling pathways that determine endometrial receptivity

Published online by Cambridge University Press:  18 September 2024

Yumei Wang Open the ORCID record for Yumei Wang [Opens in a new window] ,
Zhongxiang Ji ,
Ni Yao ,
Ximin Hu ,
Ran Zhou ,
Xingping Wang  and
Zhuoma Luoreng
Yumei Wang
Affiliation:
College of Animal Science and Technology, Ningxia University, Yin Chuan, NingXia, 750021, China
Zhongxiang Ji
Affiliation:
College of Animal Science and Technology, Ningxia University, Yin Chuan, NingXia, 750021, China
Ni Yao
Affiliation:
College of Animal Science and Technology, Ningxia University, Yin Chuan, NingXia, 750021, China
Ximin Hu
Affiliation:
College of Animal Science and Technology, Ningxia University, Yin Chuan, NingXia, 750021, China
Ran Zhou
Affiliation:
College of Animal Science and Technology, Ningxia University, Yin Chuan, NingXia, 750021, China
Xingping Wang*
Affiliation:
College of Animal Science and Technology, Ningxia University, Yin Chuan, NingXia, 750021, China
Zhuoma Luoreng*
Affiliation:
College of Animal Science and Technology, Ningxia University, Yin Chuan, NingXia, 750021, China
*
Corresponding authors: Xingping Wang; Email: wxp@nxu.edu.cn; Zhuoma Luoreng; Email: luorenzhuoma@nxu.edu.cn
Corresponding authors: Xingping Wang; Email: wxp@nxu.edu.cn; Zhuoma Luoreng; Email: luorenzhuoma@nxu.edu.cn
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Summary

Endometrial receptivity is the ability of the endometrium to accept embryos. Thus, endometrial receptivity dysfunction is an important factor leading to embryo implantation failure. A good endometrial receptivity provides a suitable environment for embryo implantation, improving the embryo implantation rate. The “implantation window” stage, or the receptive stage of the endometrium, is regulated by various hormones, genes, proteins and cytokines, among which microRNAs (miRNAs) and their target genes have a regulatory effect on endometrial receptivity. This review outlines the relationship between endometrial receptivity and pregnancy, the mRNAs and related signalling pathways that regulate endometrial receptivity, and the regulatory role of miRNA in endometrial receptivity, providing a deeper understanding of the regulatory mechanisms of miRNA on endometrial receptivity in humans and animals and reference for the endometrial receptivity-related research.

Keywords

miRNAendometrial receptivityembryo implantationendometrial epithelial cells

Information

Type
Review Article
Information
Zygote , Volume 32 , Issue 4 , August 2024 , pp. 261 - 270
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Copyright
© The Author(s), 2024. Published by Cambridge University Press

Introduction

Endometrial receptivity is the ability of the endometrium to allow normal embryo implantation. It is the intricate process undertaken by the endometrial tissue to prepare for blastocyst implantation and pregnancy initiation. A good endometrial receptivity provides opportunities for embryo attachment, invasion and development, culminating in a new individual and species continuation (Neykova et al., Reference Neykova, Tosto, Giardina, Tsibizova and Vakrilov2022; Lessey and Young, Reference Lessey and Young2019). Embryo implantation occurs during the implantation window, a mid-secretory phase of the menstrual cycle. Many molecular pathways involving hormones, adhesion molecules, cytokines and growth factors synchronize the implantation window during this phase. Thus, a loss of synchronisation or failure to achieve endometrial receptivity can lead to a miscarriage or infertility (Governini et al., Reference Governini, Luongo, Haxhiu, Piomboni and Luddi2021; Blanco-Breindel et al., Reference Blanco-Breindel, Singh and Kahn2023).

Mammals successfully implant embryos only when the endometrium is in a receptive state, during which the endometrial epithelial cells (EECs) are reshaped to accept embryo implantation. Generally, embryo implantation requires a two-way communication between the blastocyst and the receptive endometrium, with poor quality blastocysts or defective endometrial receptivity leading to an implantation failure (Makrigiannakis et al., Reference Makrigiannakis, Makrygiannakis and Vrekoussis2021; Paulson and Comizzoli, Reference Paulson and Comizzoli2021; Bui et al., Reference Bui, Timmons and Young2022). During the early implantation stage, the EECs undergo epithelial-mesenchymal transition (EMT) to prepare for subsequent embryo implantation. Subsequently, the endometrial stromal cells (ESCs) undergo decidualization to create a favourable developmental environment for the embryo. Based on this, the EMT and decidualization are crucial for maintaining a good endometrial receptivity. A good endometrial receptivity is the biological basis for embryo implantation and normal development (Crha et al., Reference Crha, Ventruba, Zakova, Jeseta, Pilka, Lousova and Papikova2019; Cai et al., Reference Cai, Xu, Zhang, Zhang, Wang, Mei, Zhang, Zhou, Zhen, Kang, Yue, Sun, Jiang and Yan2022). Therefore, improving endometrial receptivity is a key factor in increasing pregnancy rates.

This article provides an overview of mRNA and its related signalling pathways that regulate endometrial receptivity, as well as the regulatory role of miRNA in endometrial receptivity. It provides an important reference for a deeper understanding of the molecular regulatory mechanisms of miRNA on human and animal endometrial receptivity.

mRNAs regulating endometrial receptivity

Homeobox (HOX)

HOX is important in cell proliferation and differentiation and is the main regulatory factor for cell identity and fate during embryonic development (Steens and Klein, Reference Steens and Klein2022; Smith et al., Reference Smith, Zyoud and Allegrucci2019). For example, HOXA10 can bind to the E-cadherin promoter region and directly regulate its expression, thereby improving endometrial receptivity, which subsequently increases embryo adhesion and implantation (Zhang et al., Reference Zhang, Liu, Liu, Song, Zhou and Cao2017). Besides, the mechanism of metformin treatment, which enhances endometrial receptivity, is associated with the upregulation of the HOXA10 gene (Cheng et al., Reference Cheng, Li, Ying, Lv, Qu, McGowan, Lin and Zhu2022). Notably, HOXA9, HOXA11 and HOXD10 are involved and highly expressed during endometrial receptivity. The embryo implantation rate decreases when the HOXA9, HOXA11 and HOXA10 genes are silenced in the mouse uterus (Kara et al., Reference Kara, Ozcan, Aran, Kara and Yilmaz2019; Xu et al., Reference Xu, Geerts, Bu, Ai, Jin, Li, Zhang and Zhu2014). In addition, the expression levels of HOXA10 and HOXA11 are significantly reduced in women with endometriosis compared to the non-endometriotic controls, which potentially significantly affects endometrial remodelling and the expression of endometrial receptivity markers (Jana et al., Reference Jana, Banerjee, Mukherjee, Chakravarty and Chaudhury2013). Therefore, a high expression of HOX genes, including HOXA10, HOXA9, HOXA11 and HOXD10, can serve as markers for achieving endometrial receptivity.

Interleukin (IL)

ILs are lymphokines excreted by the white blood cell and other immune cell (Khan et al., Reference Khan, Farooq, Hwang, Haseeb and Choi2023). Among them, IL-1 is positively correlated with endometrial receptivity in patients with polycystic ovary syndrome (PCOS); thus, it is a therapeutic target for PCOS to improve endometrial receptivity (Zhao et al., Reference Zhao, Shan, Li, Jiang and Qu2019). In addition, the production of IL-1β promotes oocyte maturation, fertilisation, and endometrial receptivity, thereby promoting embryo implantation (Rehman et al., Reference Rehman, Jawed, Zaidi, Baig and Ahmeds2015). Specifically, IL-1β is highly expressed in the mid-luteal phase of implantation and positively correlated with endometrial thickness, serum estradiol and progesterone levels, implying that IL-1β improves endometrial receptivity, which promotes embryonic development (Wang et al., Reference Wang, Huang, Jiang, Du, Zhou, Jiang, Yan, Xing, Hou, Zhou, Sun and Yan2018). Additionally, IL-10 promotes the attachment of BeWo spheroids to Ishikawa cells and increases HOXA10 expression through phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby promoting endometrial receptivity (Wang et al., Reference Wang, Huang, Jiang, Du, Zhou, Jiang, Yan, Xing, Hou, Zhou, Sun and Yan2018). IL-33 promotes endometrial receptivity by increasing HOXA10 expression through the phosphorylation of STAT3. Decreased intracellular IL-33 impairs endometrial receptivity in women with adenomyosis (He et al., Reference He, Teng, Hao, Zhao, Chen, Li and Yan2022). In summary, the positive correlation between IL members, such as IL-1, IL-1β, IL-10 and IL-33, and endometrial receptivity suggests that IL promotes endometrial receptivity and embryo implantation.

Leukaemia inhibitory factor (LIF)

LIF is a cytokine in the IL-6 family, which regulates the adhesion characteristics of EECs, enhances endometrial receptivity, and promotes embryo implantation and pregnancy (Camargo-Diaz et al., Reference Camargo-Diaz, Garcia, Ocampo-Barcenas, Gonzalez-Marquez and Lopez-Bayghen2017). Based on in vitro and in vivo studies on the effect of the Cnidium officinale Makino (CoM) roots on endometrial receptivity using embryo implantation models, CoM enhances the adhesion of JAr cells to Ishikawa cells by activating the expression of LIF and integrin, thereby enhancing endometrial receptivity (Chung et al., Reference Chung, Park, Lee, Kim, Kim, Choi and Ha2019). Hajipour et al. (Reference Hajipour, Sambrani, Ghorbani, Mirzamohammadi and Nouri2021) also revealed that the upregulation of LIF is one of the mechanisms by which sildenafil citrate enhances endometrial receptivity. In addition, various bioactive substances such as paeoniflorin increase the adhesion of JAr cells derived from the trophoblastic ectoderm to Ishikawa cells in the endometrium by activating LIF expression, which enhances endometrial receptivity (Eun-Yeong et al., Reference Eun-Yeong, Tae-Wook, Hee-Jung, Ki-Tae, Yeon-Seop, Syng-Ook, Jun-Yong, Hyung, Sooseong and Myeong2019; Park et al., Reference Park, Choi, Kim, Chung, Kim, Joo, Ryu, Bae and Ha2021; Choi et al., Reference Choi, Chung, Park, Jung, Lee, Kim and Ha2017). Therefore, activating LIF expression enhances the adhesion between JAr cells and Ishikawa cells, promoting endometrial receptivity.

Vascular endothelial growth factor (VEGF)

Vascular endothelial growth factor (VEGF), or vascular permeability factor, is a highly specific endothelial cell mitogen and the most important factor regulating angiogenesis (Dvorak, Reference Dvorak2000). VEGF stimulates embryo implantation by promoting embryonic development, improving endometrial receptivity, and enhancing the interaction between developing embryos and the endometrium (Guo et al., Reference Guo, Yi, Li, Wang, Wang and Chen2021; Zarei et al., Reference Zarei, Nikpour, Rashidi, Eskandari and Aboutorabi2019). For example, Bu Shen Zhu Yun Decoction activates the mitogen-activated protein kinase (MAPK) signalling pathway by upregulating VEGF and VEGF receptor-2, thereby improving endometrial receptivity and embryo implantation rate (Li et al., Reference Li, Jiang, Wei, Geng, He and Du2019). In addition, Tiaojing Zhu Yun Formula improves endometrium receptivity and facilitates embryo implantation of controlled ovarian hyperstimulation (COH) rats by upregulating VEGF and enhancing the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signalling pathway (You et al., Reference You, Du, Zhang, Wang, Lv and Zeng2022a). Endometrial macrophages modulate uterine receptivity by regulating the expression of VEGFA, thereby affecting embryo implantation (Wang et al., Reference Wang, Xie, Liu, Gong, Shi, Wei and Quan2016). In summary, the upregulation of VEGF improves endometrial receptivity and promotes embryo implantation and development.

Other mRNAs that regulate endometrial receptivity

Other mRNAs are also closely related to endometrial receptivity in various species such as mouse, rat, human and goat (Table 1). Their expression trends are also clear; thus, they can serve as potential biomarkers of endometrial receptivity.

Table 1.

Other mRNAs regulating endometrial receptivity

miRNA-mediated regulation of the key signalling pathways in endometrial receptivity

MicroRNAs (miRNAs) are a class of non-coding single-stranded ribonucleic acid (RNA) molecules, typically 20-24 nt in length encoded by endogenous genes. MiRNA-encoding genes are transcribed by RNA polymerase II to generate primary transcripts, which are then processed into small RNAs of approximately 21 nucleotides by RNase III endonucleases DROSHA and DICER. All miRNAs are loaded into Argonaute protein in RNA-induced silencing complex and act as post-transcriptional regulators by binding to the 3’-untranslated region of mRNA (Stavast and Erkeland, Reference Stavast and Erkeland2019; Michlewski and Caceres, Reference Michlewski and Caceres2019). MiRNAs play an important regulatory role in endometrial receptivity and the formation of related factors during embryo implantation (Liang et al., Reference Liang, Wang and Wang2017; Shekibi et al., Reference Shekibi, Heng and Nie2022; Goharitaban et al., Reference Goharitaban, Abedelahi, Hamdi, Khazaei, Esmaeilivand and Niknafs2022). Notably, miRNAs regulate endometrial receptivity-related key genes to promote or suppress endometrial receptivity by activating or inhibiting signalling pathways, such as PI3K/Akt, extracellular signal-regulated kinase/mechanistic target of rapamycin (ERK/mTOR), NF-κB, Wnt/β-Catenint and LIF/STAT3 signalling pathways.

Regulation of gene expression by miRNA via the PI3K/Akt signalling pathway

The PI3K/Akt signalling pathway plays a crucial role in cell functions such as proliferation, adhesion, invasion, migration, metabolism and survival through phosphorylation or dephosphorylation. It also plays a role in angiogenesis, endometrial receptivity and successful embryo implantation (Shen et al., Reference Shen, Liu, Ma and Zhu2023). In addition, acupuncture and moxibustion improve endometrial angiogenesis by activating the PI3K/Akt signalling pathway, and increase endometrial receptivity and implantation sites in PCOS rats (Xing et al., Reference Xing, Chen, He, He, Sun, Xu, Wang, Zhuang, Ren, Chen, Yang, Cheng and Zhao2022). Liu et al. (Reference Liu, Zhang, Liu, Cui, Che, An, Song and Cao2018) also revealed that circ-8073 regulates CEP55 by sponging miR-449a in dairy goat EECs, promoting the proliferation of the EECs via the PI3K/Akt/mTOR pathway, and regulating endometrial receptivity in dairy goat (Figure 1). In addition, Wang et al. (Reference Wang, Ge, Zhang, Wang, Lu, Gou, Gou, Xu, Ma and Zhang2023) confirmed that human chorionic gonadotropin activates the PI3K/Akt/eNOS pathway via the miR-126-3p/PIK3R2 axis, promoting EEC proliferation and improving endometrial receptivity (Figure 1). Moreover, Talin1 and phosphatidylinositol 4,5-phosphate kinase (PIPK1) competitively bind miR-1285-3p to activate the PI3K/Akt signalling pathway. The activation of the PI3K/AkT signalling pathway further promotes the expression of ERK2, FAK and Vinculin, αvβ3 molecules crucial in the embryo implantation process, promoting the adhesion ability of EECs to the embryo (Li, Reference Li2019) (Figure 1). In summary, miRNA promotes the activation of the PI3K/Akt signalling pathway by regulating the expression of target mRNA, which alters the expression of endometrial receptivity key genes, thereby improving endometrial receptivity.

Figure 1.

The mechanism of miRNA in regulating endometrial receptivity via the PI3K/AkT signalling pathway. Some miRNAs promote the activation of the PI3K/Akt signalling pathway by regulating the expression of target mRNA, thereby altering the expression of key genes involved in endometrial receptivity, consequently improving endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Regulation of gene expression by miRNA via the ERK/mTOR signalling pathway

Various studies have revealed that the mTOR pathway is important in endometrial receptivity (Qi et al., Reference Qi, Wang, Hou, Wu, Xu and Pang2022; Niknafs et al., Reference Niknafs, Shokrzadeh, Reza and Bakhtiar2022). For example, dexamethasone disrupts endometrial receptivity by altering the expression of miR-223, miR-200a, LIF, Muc1, SGK1 and ENaC via the ERK1/2-mTOR pathway (Shariati et al., Reference Shariati, Niknafs, Seghinsara, Shokrzadeh and Alivand2019). On the contrary, fluhydrocortisone (Hesam et al., Reference Hesam, Seghinsara, Shokrzadeh and Niknafs2019) and calcitonin (Shokrzadeh et al., Reference Shokrzadeh, Alivand, Abedelahi, Hessam and Niknafs2018) improve endometrial receptivity by regulating the expression of endometrial receptivity-related genes (HB-EGF, MSX.1 and miRNA Let-7a) and activating the ERK1/2-mTOR pathway (Figure 2). Additionally, Cui et al. (Reference Cui, Liu, Yang, Che, Guo, Han, Zhu, Cao, An, Zhang and Song2020) revealed that miR-184 targets and inhibits the expression of STC2 via the RAS/RAF/MEK/ERK signalling pathway, thereby promoting the expression of FOXM1 and VEGF and apoptosis of EECs, consequently promoting endometrial receptivity in dairy goats (Figure 2). In summary, miRNA promotes endometrial receptivity by activating the ERK/mTOR signalling pathway to regulate endometrial receptivity-related genes.

Figure 2.

The mechanism of miRNA in regulating endometrial receptivity via the ERK/mTOR signalling pathway. MiR-184 regulates genes associated with endometrial receptivity by activating the ERK/mTOR signalling pathway, thus promoting endometrial receptivity. Some drug treatments regulate the expression of endometrial receptivity-related genes and miRNAs via the ERK/mTOR signalling pathway, consequently altering endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Regulation of gene expression by miRNA via the NF-κB signalling pathway

Progesterone and melatonin improve endometrial receptivity in mice and cows, increasing their pregnancy rates, which is closely related to the NF-κB signalling pathway (Feng et al., Reference Feng, Qin, Li, Olugbenga, Huang, Li, Zhao and Zheng2022; Guan et al., Reference Guan, Liu, Zhou, Dai, Wang, Fang, Jia and Li2022; Zheng et al., Reference Zheng, Qin, Feng, Li, Huang, Li, Zhao and Huang2022). Notably, high progesterone levels during early pregnancy in cows induce high expression of miR-20b. MiR-20b blocks the NF-κB signalling pathway by negatively regulating NCOA3 and inhibits the immune response of bovine EECs, crucial in uterine tissue remodelling, changes in uterine immune microenvironment and placental formation (Yang, Reference Yang2021) (Figure 3). In addition, miR-182-5p activates the NF-κB signalling pathway by negatively regulating the target gene NDRG1, which reduces the E-cadherin expression, inhibits endometrial receptivity and causes embryo implantation failure (Yu et al., Reference Yu, Kang, Jeong, Lee, Jeon, Kim, Lee, Han, Kang and Park2022) (Figure 3).

Figure 3.

The mechanism of miRNA in regulating endometrial receptivity via the NF-κB signalling pathway. MiRNA typically inhibits target mRNA to activate NF-κB signalling pathway inhibits endometrial receptivity. MiRNA typically inhibits target mRNA to block NF-κB signalling pathway promotes endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

The NF-κB signalling pathway is also an important pathway regulating inflammation (Capece et al., Reference Capece, Verzella, Flati, Arboretto, Cornice and Franzoso2022). Interestingly, enhancing the endometrium inflammatory process reduces endometrial receptivity (Zhang et al., Reference Zhang, Li, Xu, Wang, Li and Wang2021; Pirtea et al., Reference Pirtea, Cicinelli, De Nola, de Ziegler and Ayoubi2021). Therefore, some of the miRNAs in the NF-κB signalling pathway could be regulating the expression of inflammatory factors, interfering with the embryo implantation process, and reducing the ability of the endometrium to receive embryos. In summary, miRNAs often activate the NF-κB signalling pathway, suppressing endometrial receptivity. Therefore, future studies should explore the miRNAs that inhibit the NF-κB signalling pathway to improve endometrial receptivity.

Regulation of gene expression by miRNA via the Wnt/β-catenin signalling pathway

The Wnt/β-catenin signalling pathway is a highly conserved pathway involved in various processes such as cell development, proliferation, differentiation, apoptosis and autophagy. It plays a crucial role in embryonic development and maintaining dynamic homeostasis in the body (Ma et al., Reference Ma, Yu, Zhang, Wu and Deng2023; Liu et al., Reference Liu, Hao and Yang2023). Integrin-linked kinase (ILK) (Chen et al., Reference Chen, Ni, Han, Zhou, Zhu and Zhang2020) and baicalin (Zhang et al., Reference Zhang, Zhang, Bulbul, Shan, Wang and Yan2015) promote endometrial receptivity and embryo implantation via the Wnt/β-catenin signalling pathway (Figure 4). Zheng et al. (Reference Zheng, Zhang, Yang, Cui, Sun, Liang, Qin, Yang, Liu and Yan2017) also revealed the miR-200c targeted inhibition of fucosyltransferase IV (FUT4) expression while reducing the glycoprotein CD44 α1,3-fucosylation inactivates the Wnt/β-catenin signalling pathway, leading to endometrial receptivity dysfunction (Figure 4). Besides, miR-543 inhibits MAPK expression and inactivates the Wnt/β-catenin pathway, inducing the inhibition of the EMT of ESCs by transforming growth factors β (Wang et al., Reference Wang, Liu, Wei, Yuan, Zhao, Huang, Ma and Yang2021) (Figure 4). In summary, the Wnt/β-catenin signalling pathway plays an important regulatory role in initiating endometrial receptivity. The miRNAs often activate the Wnt/β-Catenin signalling pathway, promoting endometrial receptivity, or suppress the Wnt/β-catenin signalling pathway, inhibiting endometrial receptivity.

Figure 4.

The mechanism of miRNA in regulating endometrial receptivity via the Wnt/β-catenin signalling pathway. MiRNA typically inhibits target mRNA, thereby inactivating the Wnt/β-catenin signalling pathway, leading to the inhibition of endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Regulation of gene expression by miRNA via the LIF/STAT3 signalling pathway

The LIF/STAT3 signalling pathway also affects endometrial receptivity (Liang et al., Reference Liang, Liu, Jin, Liang, Fu, Gu and Yang2018, Reference Liang, Li, Chen, Liang, Qin, He, Shi, Tan and Wang2021; Hu et al., Reference Hu, Liang, Luo, Gu, Chen, Fu, Zhu, Lin, Diao, Jia and Yang2019). For example, implantation failure in subclinical hypothyroidism rats is related to abnormal LIF/STAT3 signalling (Shan et al., Reference Shan, Zhou, Peng, Wang, Shan and Teng2019). Generally, COH induces endometrial receptivity dysfunction during the implantation window. However, electroacupuncture therapy reduces cell adhesion molecules such as E-Cadherin, β-catenin and CLDN1, which activates the LIF/STAT3 signalling pathway, improves endometrial receptivity, and promotes blastocyst implantation in COH rats (You et al., Reference You, Du, Zhang, Wang, Lv and Zeng2021) (Figure 5). In addition, miR-223-3p expression inhibits the LIF/STAT3 signalling pathway in the rat endometrium. However, electroacupuncture therapy enhances endometrial receptivity by inhibiting miR-223-3p expression in the LIF/STAT3 signalling pathway (You et al., Reference You, Du, Zhang, Wang, Lv and Zeng2022b) (Figure 5). In summary, miRNA promotes endometrial receptivity by regulating the LIF/STAT3 signalling pathway. However, there are few reports on the specific regulatory effects of miRNA on endometrial receptivity. Therefore, the LIF/STAT3 signalling pathway is a potential signalling pathway for miRNA regulation of endometrial receptivity, though more research is needed.

Figure 5.

The mechanism of miRNA in regulating endometrial receptivity via the Leukaemia inhibitory factor (LIF)/STAT3 signalling pathway. Electroacupuncture therapy reduces cell adhesion molecules, thereby activating the LIF/STAT3 signalling pathway, which improves endometrial receptivity. Electroacupuncture therapy activates the LIF/STAT3 signalling pathway by inhibiting the expression of miR-223-3p, thereby enhancing endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

The regulatory role of miRNA in endometrial receptivity

A good endometrial receptivity is a prerequisite for successful embryo implantation. Therefore, scholars are constantly exploring methods to improve endometrial receptivity. Many miRNAs regulate endometrial receptivity in mouse and other animals and can serve as useful diagnostic and therapeutic targets for successful embryo implantation, providing reference for relevant scientific research and clinical application (Table 2).

Table 2.

The regulatory role of miRNA in endometrial receptivity

The regulatory effect of miRNA on endometrial receptivity in mouse

Cullin 3 (CUL3), an E3 ubiquitin ligase, interacts with beclin 1 (BECN1), thereby promoting K48-linked ubiquitination and degradation of BECN1.In mice, miR-23a-3p inhibits target gene CUL3 expression by negatively regulating β-Catenin ubiquitination to promote endometrial receptivity and embryo implantation (Huang et al., Reference Huang, Chen, Fan and Hu2020). According to Akbar et al. (Reference Akbar, Ullah, Rahman, Cheng, Pang, Jin, Wang, Huang and Sheng2020), inhibiting miR-183-5p also significantly reduces the embryo implantation rate and increases the expression of target gene catenin alpha 2 (CTNNA2) in vivo using a mouse pregnancy model, implying that miR-183-5p regulates endometrial receptivity and enhances embryo implantation. Another study revealed that miR-let-7a/g enhances mouse endometrial receptivity by inhibiting the Wnt signalling pathway by negatively regulating oestrogen and progesterone, improving embryo attachment and growth related to implantation (Li et al., Reference Li, Liu, Chiu and Yeung2020).

Poly (ADP-ribose) polymerase 2 (PARP-2) is a gene involved in endometrial receptivity for trophoblast implantation. Moreover, miR-149 inhibits endometrial receptivity by downregulating the target gene PARP-2 and upregulating caspase-8 (Verma et al., Reference Verma, Soni, Chadchan, Maurya, Soni, Sarkar, Pratap and Jha2022; Soni et al., Reference Soni, Chadchan, Gupta, Kumar and Kumar2021). At the same time, miR-223-3p and miR-181 inhibit endometrial receptivity and embryo implantation in mice by targeting and downregulating the LIF, a key regulatory factor for endometrial receptivity (Dong et al., Reference Dong, Sui, Huang, Wang, Hu, Xiong, Wang and Zhang2016; Chu et al., Reference Chu, Zhong, Dou, Wang, Li, Wang, Shi, Mei and Wu2015). On the contrary, electroacupuncture therapy enhances endometrial receptivity by inhibiting the expression of miR-223-3p on the LIF/STAT3 signalling pathway (You et al., Reference You, Du, Zhang, Wang, Lv and Zeng2022b). Yuan et al. (Reference Yuan, Feng, Mao, Huang, Liu, Li and Jiang2021) also revealed that miR-494-3p targeting LIF regulates endometrial receptivity via the PI3K/Akt/mTOR pathway, and inhibiting miR-494-3p increases the LIF and VEGF expression levels, thereby increasing endometrial receptivity in mice. Besides, miR-183 inhibits embryo implantation by regulating HB-EGF and LAMC1 in the mouse uterus, suggesting that miR-183 inhibits endometrial receptivity (Cao et al., Reference Cao, Liang, Feng, Shi, Tan and Wang2020). Exosomes miR-205-5p upregulate E-cadherin by targeting ZEB1, thereby improving endometrial receptivity (Yu et al., Reference Yu, Jeong, Noh, Jeon, Lee, Kang, Kim, Lee, Han, Kang and Park2023).

The regulatory effect of miRNA on endometrial receptivity in human

miR-145 and miR-199 transfection into Ishikawa cells significantly reduces the podocalyxin (PODXL) expression, which significantly promotes the endometrial receptivity of the Ishikawa monolayer (Shekibi et al., Reference Shekibi, Heng and Nie2022). Polychlorinated biphenyls induce endometrial receptivity dysfunction by disrupting the interaction between the key gene miR-30d regulating endometrial receptivity and the EMT process. Snai1 is targeted by miR-30d and induced by polychlorinated biphenyls (Cai et al., Reference Cai, Liu, Hu, Jiang, Qiu, Sha, Wang, Zuo and Ren2016). Lack of miR-30d in the mother or embryo results in a significant downregulation of the endometrial receptivity markers, which reduces the implantation rate and damages embryonic growth (Balaguer et al., Reference Balaguer, Moreno, Herrero, Gonzalez-Monfort, Vilella and Simon2019). In addition, Kong et al. (Reference Kong, Sun, Zhang, Ding, Zhang, Cheng, Diao, Yan, Zhang, Fang, Zhen, Hu, Sun and Yan2016) revealed that miR-133b targets SGK1 to increase HOXA10 expression and promote the attachment of BeWo spheres to Ishikawa cells, which induce endometrial receptivity and embryo attachment. Shi et al. (Reference Shi, Tan, Liang, Cao, Wang, Liang, Chen and Wang2021) also revealed that miR-1290 is an extracellular vesicle derived from placental trophoblasts, which stimulates the interaction between the endometrium and embryo by targeting LHX6, thereby promoting endometrial receptivity.

Moreover, miR-192-5p is an upstream regulatory factor of ARHGAP19, which promotes the transition of EECs from non-receptive to receptive states by regulating the remodelling of connexin and membrane-related cytoskeleton (Liang et al., Reference Liang, Li, Chen, Liang, Qin, He, Shi, Tan and Wang2021). Another study revealed that miR-192-5p inhibits endometrial receptivity by hindering epithelial transformation during embryo implantation (Liang et al., Reference Liang, Cao, Zhang, Liu, Tan, Shi, Chen, Liang and Wang2020). Therefore, sustained high levels of miR-192-5p are harmful to embryo implantation. At the same time, miR-125b inhibits EEC migration and invasion by downregulating MMP26, which weakens the embryo attachment and subsequent endometrial invasion, leading to decreased endometrial receptivity (Chen et al., Reference Chen, Zhao, Yu, Li and Qiao2016). The overexpression of miR-146a-3p also significantly inhibits the expression of LIF, integrin3, claudin4 and DKK1 in EECs, which inhibits endometrial receptivity (Wei et al., Reference Wei, Wang, Li and Guo2021). In the endometrium of infertile women, the overexpression of miR-29c and downregulation of COL4A1 reduces the EECs adhesion ability in vitro, suggesting that miR-29c plays a role in the secretion phase of infertile women, decreasing receptivity and implantation success rate (Griffiths et al., Reference Griffiths, Van Sinderen, Rainczuk and Dimitriadis2019). MiR-23b-3p also regulates the adhesion of human EECs, suggesting that it may be a key regulator of endometrial epithelial adhesion and endometrial receptivity (Barton et al., Reference Barton, Zhou, Santos, Menkhorst, Yang, Tinn, Ang, Lucky and Dimitriadis2023).

Furthermore, research has also revealed that the downregulation of miR-543 affects embryo implantation, leading to endometriosis-related infertility (Yang et al., Reference Yang, Wu, Ma, Pan, Wang and Yan2019). Another study revealed that miR-31 is the best potential biomarker for endometrial receptivity and may function through immunosuppressive mechanisms (Kresowik et al., Reference Kresowik, Devor, Van Voorhis and Leslie2014). MiR-124-3p negatively impacts embryo implantation by suppressing endometrial receptivity formation and embryo development through targeted inhibition of LIF, MUC1 and BCL2 expression (Yao et al., Reference Yao, Kang, Chen, Shi and Jin2024).

The regulatory effect of miRNA on endometrial receptivity in livestock

The miR-449a/c expression in the uterine cycle is associated with endometrial development (Naydenov et al., Reference Naydenov, Nikolova, Apostolov, Glogovitis, Salumets, Baev and Yahubyan2022). MiR-449a promotes endometrial receptivity by regulating the apoptosis of goat ESCs and negatively regulating LGR4 (An et al., Reference An, Liu, Zhang, Liu, Zhao, Chen, Ma, Li, Cao and Song2017). Similarly, miR-182 promotes endometrial receptivity by downregulating pleiotrophin and regulating apoptosis-related genes and endometrial receptivity marker genes such as osteopontin (OPN), cyclooxygenase-2 (COX-2 and prolactin receptor ( PRLR) in dairy goat EECs (Zhang et al., Reference Zhang, Liu, Liu, Song, Zhou and Cao2017). miR-26a also regulates the expression of OPN, VEGF, COX-2 and prolactin (PRL) in endometrial cells, thereby promoting endometrial receptivity (Zhang et al., Reference Zhang, Liu, Liu, Ma, Zhou, Song and Cao2018). At the same time, miR-26a promotes the proliferation of EECs and induces ESC apoptosis via the PTEN-PI3K/Akt pathway in dairy goats (Zhang et al., Reference Zhang, Liu, Liu, Ma, Zhou, Song and Cao2018).

Furthermore, miR-15b is competitively bound by lncRNA882 and LIF in EECs, which upregulates LIF and induces endometrial receptivity in dairy goats (Zhang et al., Reference Zhang, Liu, Cui, Che, Liu, An, Cao and Song2019). Liu et al. (Reference Liu, Zhang, Yang, Cui, Che, Liu, Han, An, Cao and Song2020) also revealed that miR-34a and miR-34c are highly expressed in goats and induce apoptosis of EECs by binding to circ-8073 and CEP55 via the RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways, which induce endometrial receptivity in dairy goats. The apoptosis of EECs is an important process for endometrial receptivity induction and embryo implantation. However, bta-miR-200b affects the apoptosis of bovine EECs by targeting MYB genes, thereby promoting endometrial receptivity (Lyu et al., Reference Lyu, Zhai, Zhu, Shi, Chen, Zhang, Zhang and Wang2023). In pigs, knocking down ssc-miR-21-5p inhibits Akt phosphorylation by targeting PDCD4, which hinders endometrial receptivity, decreasing the embryo implantation rate (Hua et al., Reference Hua, Zhang, Li, Lian, Liu, Gao, Wang and Lei2020). Besides, in buffalo, miR-1246 secreted by the trophoblast reduces the expression of endometrial receptivity gene (MUC1 and β-catenin), implying that miR-1246 is a potential marker for buffalo endometrial receptivity (Dubey et al., Reference Dubey, Batra, Sarwalia, Nayak, Baithalu, Kumar and Datta2023). In the same line, miR-134-5p inhibits the proliferation of sheep ESCs by inhibiting the target gene CREB1, thereby inhibiting the establishment of endometrial receptivity (Li et al., Reference Li, Yao, Li, Guo, Deng, Liu, Yang, Fan, Yang, Zhu and Wang2023).

Conclusions and future perspectives

endometrial receptivity is crucial for successful embryo implantation and pregnancy. endometrial receptivity dysfunction induces EEC attachment failure or poor embryo reception, which decreases the pregnancy rate. Various factors influence endometrial receptivity via multiple signalling pathways, including mRNA and miRNAs, which play a crucial role in endometrial receptivity induction by participating in the signalling pathways, such as the PI3K/Akt signalling pathway. Although the regulatory mechanisms of some miRNAs regulating endometrial receptivity have been studied, the regulatory mechanism of miRNAs on endometrial receptivity is still unclear. Therefore, further research on the molecular regulatory network of miRNA on endometrial receptivity is needed to improve endometrial receptivity and pregnancy rates. In addition, miRNAs should be explored as biomarkers or therapeutic targets for detecting or improving endometrial receptivity in maternal therapy.

Acknowledgements

We would like to thank the editor of MogoEdit professional English editing company (Mogo Internet Technology Co., LTD, Shaanxi, China) for help in the preparation of this manuscript.

Author contributions

The idea of the manuscript was created by Yumei Wang. All authors contributed to the initial conception and creation structure of the manuscript. Yumei Wang wrote the first draft. All authors contributed to the improvement and final edition of the manuscript.

Competing interests

The authors declare no conflict of interest.

Funding

This research was supported by Project of Ningxia Hui Autonomous Region Key Research and Development Program (No. 2021BEF02029); Project of Ningxia Hui Autonomous Region Key Research and Development Program (Special Talent Introduction) (No. 2020BEB04006); and the earmarked fund for CARS (No. CARS-36).

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Figure 0

Table 1. Other mRNAs regulating endometrial receptivity

Figure 1

Figure 1. The mechanism of miRNA in regulating endometrial receptivity via the PI3K/AkT signalling pathway. Some miRNAs promote the activation of the PI3K/Akt signalling pathway by regulating the expression of target mRNA, thereby altering the expression of key genes involved in endometrial receptivity, consequently improving endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Figure 2

Figure 2. The mechanism of miRNA in regulating endometrial receptivity via the ERK/mTOR signalling pathway. MiR-184 regulates genes associated with endometrial receptivity by activating the ERK/mTOR signalling pathway, thus promoting endometrial receptivity. Some drug treatments regulate the expression of endometrial receptivity-related genes and miRNAs via the ERK/mTOR signalling pathway, consequently altering endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Figure 3

Figure 3. The mechanism of miRNA in regulating endometrial receptivity via the NF-κB signalling pathway. MiRNA typically inhibits target mRNA to activate NF-κB signalling pathway inhibits endometrial receptivity. MiRNA typically inhibits target mRNA to block NF-κB signalling pathway promotes endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Figure 4

Figure 4. The mechanism of miRNA in regulating endometrial receptivity via the Wnt/β-catenin signalling pathway. MiRNA typically inhibits target mRNA, thereby inactivating the Wnt/β-catenin signalling pathway, leading to the inhibition of endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Figure 5

Figure 5. The mechanism of miRNA in regulating endometrial receptivity via the Leukaemia inhibitory factor (LIF)/STAT3 signalling pathway. Electroacupuncture therapy reduces cell adhesion molecules, thereby activating the LIF/STAT3 signalling pathway, which improves endometrial receptivity. Electroacupuncture therapy activates the LIF/STAT3 signalling pathway by inhibiting the expression of miR-223-3p, thereby enhancing endometrial receptivity. The figure is made by WPS, which is a Chinese office software.

Figure 6

Table 2. The regulatory role of miRNA in endometrial receptivity