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Reproductive Biology and Endocrinology

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Role of microRNAs in embryo implantation

Reproductive Biology and Endocrinology201715:90

https://doi.org/10.1186/s12958-017-0309-7

Received: 5 June 2017

Accepted: 7 November 2017

Published: 21 November 2017

Abstract

Failure of embryo implantation is a major limiting factor in early pregnancy and assisted reproduction. Determinants of implantation include the embryo viability, the endometrial receptivity, and embryo-maternal interactions. Multiple molecules are involved in the regulation of implantation, but their specific regulatory mechanisms remain unclear. MicroRNA (miRNA), functioning as the transcriptional regulator of gene expression, has been widely reported to be involved in embryo implantation. Recent studies reveal that miRNAs not only act inside the cells, but also can be released by cells into the extracellular environment through multiple packaging forms, facilitating intercellular communication and providing indicative information associated with physiological and pathological conditions. The discovery of extracellular miRNAs shed new light on implantation studies. MiRNAs provide new mechanisms for embryo-maternal communication. Moreover, they may serve as non-invasive biomarkers for embryo selection and assessment of endometrial receptivity in assisted reproduction, which improves the accuracy of evaluation while reducing the mechanical damage to the tissue. In this review, we discuss the involvement of miRNAs in embryo implantation from several aspects, focusing on the role of extracellular miRNAs and their potential applications in assisted reproductive technologies (ART) to promote fertility efficiency.

Keywords

ImplantationViable embryoEndometrial receptivityMicroRNAExtracellular vesicle

Background

Embryo implantation is a crucial step of pregnancy establishment in mammals and occurs in a restricted time period, termed the “window of implantation” (WOI). During implantation, the embryo and the uterus go through synchronous development and bidirectional crosstalk, eventually establishing structural linkage and achieving material exchange.

Understanding the mechanism of implantation has a profound effect on improving reproductive efficiency. Efficiency of pregnancy in human remains relatively low (~30%), and implantation failure accounts for 75% of pregnancy loss [1]. Situation in animals is slightly more optimistic, however, embryo loss during the pre-implantation period, which is very likely to happen in pigs and horses, remains a major obstacle to successful pregnancies [2]. Also in dairy cows, early embryo loss due to the failure of maternal recognition of pregnancy is believed to account for up to 25% of failures of conception [3]. Although ART has brought solutions to some fertility problems, implantation rate has not been greatly improved, and challenges remain regarding the poor accuracy of the methods to assess embryonic viability and endometrial receptivity. Thus, more investigations are needed in order to provide practical solutions to these problems.

Strategies for implantation vary considerably among species (Table 1) [2, 4, 5].Depending on the extent of the interactions between embryonic tissue and the maternal uterus, implantation can be invasive or non-invasive [4]. Primates and rodents exhibit invasive implantation, where the trophoblast cells of the blastocyst intrude into the uterine epithelium, penetrate the basal lamina, and form hemochorial placentation. Some domestic animals such as ruminants, horses, and pigs present non-invasive implantation, where the embryonic cells remain superficial or slightly fuse with the endometrial epithelium cells (EEC), forming synepitheliochorial (ruminants) or epitheliochorial placenta (pigs and horses). However, the initial stages of implantation are common across these species and are known as the “adhesion cascade for implantation” [4]. This process involves apposition and adhesion of the hatched blastocyst to the uterine luminal epithelium. Besides, embryo viability, endometrial receptivity and embryo-maternal crosstalk are the determinants for a successful implantation despite the difference in mammalian implantation strategies [6]. Moreover, the process of implantation is under the strict regulation of ovarian hormones- estrogen and progesterone [7]. Multiple molecules such as cytokines, chemokines, growth factors, lipids, and receptors also participate in the regulation of implantation through autocrine, paracrine and juxtacrine ways [7].
Table 1

Embryo implantation in different species

Species

Arrival to the Uterine Cavity

Hatch

Conceptus Elongation

Recognition Signal of Pregnancy

Initiate Implantation

Firm Attachment

Placentation

Homo sapiens

Day 4

Day 4–5

No

Human chorionic gonadotropin (hCG)

Day 6–7

Day 8–10

Hemochorial (invasive)

Mus musculus

Day 3

Day 4

No

Prolactin (PRL)

Day 4

Day 5–6

Hemochorial (invasive)

Bos taurus

Day 4–5

Day 9–10

Yes

Interferon tau (IFNT)

Day 19

Day 40–45

Synepitheliochorial (non-invasive)

Sus scrofa

Day 2–2.5

Day 6

Yes

Estrogen

Day 12–13

Day 25–26

Epitheliochorial (non-invasive)

Ovis aries

Day 3–4

Day 7–8

Yes

Interferon tau (IFNT)

Day 14–15

Day 28–35

Synepitheliochorial (non-invasive)

Equus caballus

Day 6

Day 7–8

No

Unknown factor

Day 35–40

Day 95–105

Epitheliochorial (non-invasive)

MiRNAs are small non-coding RNAs functioning in RNA silencing and post-transcriptional regulation of gene expression [8, 9]. Recent studies show that miRNAs are expressed in blood plasma and serum [10], as well as other body fluids [11]. Nearly all types of cells are able to secrete miRNAs and the concentration of extracellular miRNAs is considered to be associated with physiological and pathological conditions of the body [12]. Some extracellular miRNAs may also be implicated in intercellular communication [13, 14].

The process of implantation involves a complex regulation system that coordinates the embryo and maternal uterus. Evidence of miRNAs regulating embryonic development and uterine functions during the peri-implantation period suggests an important role of miRNAs in this process. Moreover, the discovery of extracellular miRNAs in uterine luminal fluid (ULF) as well as in embryo culture media prompts the need to explore novel potentials of miRNAs, especially in assisted reproduction. Based on their conservativeness, stability, sensitivity and easy access, extracellular miRNAs are suggested to be valuable non-invasive biomarkers for the assessment of embryo viability and endometrial receptivity. This review summarizes available information among species and discusses the impact of miRNAs, especially extracellular miRNAs, on the process of implantation from the perspectives of key factors that influence the implantation outcomes.

Biogenesis and secretion of miRNAs

MiRNAs are small non-coding RNAs of length ~22 nt, regulating gene expression on the post-transcriptional level by targeting mRNAs for cleavage or transcriptional repression [8, 9]. Synthesized in the nucleus, a long and stem-loop carried primary miRNA is processed by Dorsha, a critical RNase III protein, to form a small hairpin-shaped miRNA, termed a pre-miRNA. Later, the pre-miRNA is translocated by protein exportin 5 (XPO5) from the nuclear pore complex to the cytoplasm, where it is cleaved by another critical RNase III protein, Dicer, into a small RNA duplex. Subsequently, the strand with a relatively unstable terminus at the 5ʹ side (in most cases) of the duplex is chosen as the guide strand to be loaded onto the Argonaute (AGO) protein family to form an effecter complex referred to as the RNA-induced silencing complex (RISC). It is the RISC that executes the function of RNA silencing or translational repression. Widely existing in cells and tissues, miRNAs are involved in a variety of biological processes. Multiple studies present the role of miRNAs in female reproduction [15]. They are involved in the regulation of oogenesis, fertilization, implantation, and placentation. Dysregulation of miRNAs has been shown to be associated with reproductive disorders, such as polycystic ovarian syndrome [15], and endometriosis [16].

Recent studies revealed that miRNAs can also be secreted into the extracellular environment. MiRNAs have been found in peripheral blood [10, 17] as well as other bio-fluids such as breast milk [18], saliva [19], urine [20], semen [21], and ULF [22]. These extracellular miRNAs stay in stable forms and are protected from endogenous RNases, showing feasibility of being non-invasive biomarkers for detection and diagnosis of pathological conditions, including cancers.

The main forms of extracellular miRNAs are associated with proteins (e.g. AGO family [23], nucleophosmin 1 [24]), bound to lipoproteins (high-density lipoprotein [25]), encapsulated into apoptotic bodies [26], or membrane-bound extracellular vesicles (EVs) [27] (Fig. 1). Among these packaging forms, protein-bound miRNAs take up the largest proportion of extracellular miRNAs in cell-free plasma and cell culture medium [28]. Though the concentration of EV-associated miRNA is far lower compared with other extracellular miRNAs, it is the most widely proved form of miRNA that can be selectively enriched, actively released by cells, and exert biological functions [29].
Fig. 1

Extracellular miRNAs participant in embryo-maternal interactions. MicroRNAs (miRNAs) are synthesised in the nucleus as primary miRNA (pri-miRNA) transcripts. Pri-miRNAs are then processed by Drosha to form nucleotide hairpin known as miRNA precursors (pre-miRNA). Later pre-miRNAs are transported by exportin-5 from nucleus into the cytoplasm where they are cleaved by Dicer into small RNA duplex. Eventually, the guide miRNA strand is loaded onto Argonaute (AGO) protein family to form the RNA-induced silencing complex (RISC),leading to either mRNA cleavage or translational repression. MiRNAs can be secreted by cells through multiple forms: associated with proteins (e.g. Argonaute family or AGO, nucleophosmin 1), bound to lipoproteins (High-density lipoprotein), encapsulated into apoptotic bodies or membrane-bound extracellular vesicles (EVs). Uterine- and embryo-derived miRNAs have been reported to be associated with exosomes and AGO1, it remains unclear whether other forms of packaging are applied by endometrial cells and/or embryonic cells (question marks)

EVs are membrane vesicles released by cells and serve as vehicles transporting lipid, proteins and nucleic acids, including miRNAs [30]. According to their size and secretory manner, EVs can be divided into microvesicles (100-1000 nm in diameter) and exosomes (smaller than 150 nm in diameter). All EVs have specific molecules on the surface enabling them to be targeted to the recipient cells. Once they reach their recipient cells, EVs would release the cargos through binding to the receptors on the membrane surface, or endocytosis, or directly fuse with the membrane [31], and modify the functions of the recipient cell. The cargos of EVs are not randomly equipped. Many studies have shown selective packaging and enrichment of individual proteins and RNAs in secreted EVs [32], suggesting that the release of specific EVs is closely related to body conditions. However, the mechanism of selective packaging is not well understood. It has been studied that EVs participate in multiple physiological and pathological processes. There is an enthusiastic interest in investigating the role of EVs in tumor genesis, invasiveness and metastasis [33, 34]. Cancer-derived EVs were shown to modify the invasive ability of the tumor cells and promote dissemination. Moreover, EVs released by tumors can act on surrounding and distant non-tumor cells to assist in creating an optimal microenvironment for tumor growth [35]. It is worth noting the common features present between the behavior of invasive embryonic cells and that of cancer cells. Similar cellular mechanisms of cell adhesion, migration, invasion, and angiogenesis are shared during implantation and cancer spread [36]. As exciting reports springing up in the field of cancer study, it is reasonable to speculate a possible and impressive role that EVs and their cargos, especially miRNAs, may play in embryo implantation [37].

MiRNAs participate in embryo implantation

MiRNAs and embryo

Intracellular miRNAs influence embryo viability

Embryo viability is one of the key factors affecting implantation. During their development from zygotes to blastocysts, mammalian embryos undergo multiple events, including cell division, proliferation, establishment of cell polarity, compaction and lineage differentiation [38]. Unlike primates and rodents, whose embryos almost immediately attach to the endometrium after shedding from the zona pellucida, the embryo of ruminants and pigs experience a process termed ‘elongation’ where the embryo goes through morphological changes, developing from a spherical shape to an oval or tubular shape, and eventually to a filamentous form before attachment [4]. In horses, the embryo undergoes an extended period of mobility, growing as an ovoid shaped conceptus without obvious morphological extension [39].

Most of the embryonic changes can be related to activity of the genome [40]. Studies in mice revealed that the genomic information within pre-implantation embryo experiences wave-like changes associated with degradation of maternal transcriptome and zygote genome activation (ZGA) [41]. Though miRNA functions as a transcriptional regulator, its role in clearance of the maternal genome remains controversial. Studies have shown that miRNA function is generally suppressed in mouse oocytes and early pre-implantation embryos [42]. MiRNA activity was inhibited prior to the 2-cell stage, which is consistent with the timing of large-scale maternal gene degradation. However, the suppression is relieved after 2-cell stage and the expression of miRNA is reactivated [43].

Despite the repression of miRNA activity during ZGA, deletion of zygotic Dgcr8, which encodes an RNA-binding protein specifically required for miRNA processing, results in embryonic arrest prior to E6.5 [42]. Knocking out other key enzymes in the miRNA biosynthesis pathway such as DICER [44] and AGO2 [45] also leads to embryonic death around gastrulation, suggesting an important role of miRNA in early embryonic development [46]. Analysis of embryos at different developing stages revealed variable trends in miRNA expression, and the role of specific miRNAs in embryonic development has been studied in multiple species. MiR-29b might contribute to disruption of DNA methylation by regulating the expression of DNMT3a/b, which leads to early embryonic developmental blockade in mice [47]. Higher expression level of miR-130b was verified in the morula and blastocyst stages of bovine IVF produced embryos, while inhibition of this miRNA significantly reduced morula and blastocyst formation [48]. By inducing embryonic stem cells to differentiate into trophectodermal cells, miR-297, miR-96, miR-21, miR-29c, let-7, miR-214, miR-125a, miR-424 and miR-376a were suggested to be involved in trophectoderm specification [49]. MiR-519d, miR-378a-5p, miR-376, and miR-155 were reported to regulate the migration and invasion ability of human trophoblast cells [5053]. MiRNAs are also implicated in regulation of embryo elongation. Functional annotations for comparisons among porcine conceptuses collected on Day10 (spherical/ovoid shape), Day 12 (filamentous form), Day 16 (elongated shape), and Day 20 (presence of evident vascularization on embryonic tissues) revealed that the differently expressed miRNAs were associated with cell cycle, cellular development, tissue morphology, inflammatory response and organismal development [54].

Environmental factors can regulate embryo viability by altering the expression of miRNAs. The mice embryo, when exposed to a progesterone-primed uterus, becomes metabolically dormant, and implantation is delayed. However, dormant embryos can be rapidly activated by a slight stimulus of estrogen and regain their implantation competency [7]. Delayed implantation in mice can be artificially induced through progesterone injection, which provides an excellent model for investigating the environmental influence on embryo implantation. Liu et al. [55] examined the miRNA profiles between dormant and activated mouse embryos and found that 45 miRNAs were differently expressed. Five of the let-7 family were down-regulated after activation. Further investigation revealed elevated let-7a reduced the number of implantation sites partly through targeting integrin beta 3. Another study in mice verified the relatively high level of let-7a in dormant embryos and found that this miRNA could also inhibit the expression of Dicer and prevent embryo implantation [56]. Although there is no evidence that delayed implantation exists in human and domestic animals, studies in mice suggest that in vivo environmental signals alter the miRNA expression patterns and eventually influence the active status of the pre-implantation embryo.

An embryo can be produced in vitro. However, production methods affect the expression pattern of miRNA in pre-implantation embryos, which in turn, affect embryo viability. In vivo fertilized porcine embryos presented lower expression of miR-24 in the blastocyst stage compared with in vitro fertilized (IVF) embryos [57]. A study in cattle revealed that elevated expression of miR-24 inhibited the development of embryo to the blastocyst stage [58]. Considering miR-24 is highly conserved across mammalian species, it may serve as biomarker for embryo quality. Down-regulated miR-199a-5p was shown in IVF mouse embryos compared with in vivo produced embryos, leading to higher glycolytic rate and lower developmental potential of blastocyst as well as reduced number of survived fetuses [59]. Together, these results reinforce the epigenetic modifications induced by the environmental factors on embryo development, since in vitro environment does not perfectly capitulate normal environment in maternal uterus [59], clarifying the functional miRNAs may help to improve the IVF system by artificially adjusting the amount of specific miRNA expression.

Extracellular miRNA profiles reflect embryo viability in vitro

Recent studies demonstrate that miRNAs exist not only within the embryo but can also be secreted by the embryo to the extracellular environment. MiRNAs have been detected in the culture media (CM) derived from IVF human and bovine embryos, with their unique expression profiles associated with the embryonic developmental and chromosomal status, sexual dimorphism, and the reproductive competence after transfer to the uterus.

Kropp et al. [60] compared the expression of several miRNAs between IVF bovine blastocysts and degenerate embryos (IVF embryos failed to develop to the blastocyst stage) and found relatively higher levels of miR-181a2, miR-196a2, miR-302c and miR-25 in degenerate embryos. They further investigated the miRNA contents in the CM and found that miR-25 was only present in CM containing embryos but not in the control media (embryo free). This finding suggested that miRNAs might be secreted by the embryos. Additionally, the absence of miR-302 in all media indicated that the secretion of miRNAs was selective. In another study, Kropp and Khatib [58] applied deep sequencing to characterize miRNA profiles in CM from IVF produced bovine blastocysts and degenerate embryos, and miR-24 was confirmed to be highly expressed in CM from degenerate embryos. Addition of miR-24 mimics to the CM from normal morula significantly reduced the development rate of embryos, partly through inhibiting cell proliferation by targeting CDKN1b, a cell cycle inhibitor. The result indicates the significant effect of extracellular miRNAs on embryo development.

The presence of miRNAs has also been confirmed in the CM from IVF human embryos. Rosenbluth et al. [61] found that miR-645 was only expressed in the control media and was found to be undetectable in CM from embryos. On the contrary, miR-372 and miR-191 were only detected in the spent CM. Moreover, the expressions of extracellular miR-372 and miR-191 were associated with IVF failure, since they were both highly detected in CM from failed IVF cycle embryos. Interestingly, a relatively higher level of miR-191 was discovered in CM from aneuploid embryos, indicating the possible role of miR-191 as a biomarker of embryo aneuploidy, a major cause of recurrent implantation failure.

Capalbo et al. [62] conducted a comprehensive analysis of miRNA profiles between the spent blastocyst culture media (SBCM) collected from human euploid blastocyst that failed to implant and blastocyst that implanted. Two miRNAs, miR-20a and miR-30c, presented significantly higher expression in SBCM from implanted blastocysts. Intriguingly, the target genes (such as PTEN, NRAS, MAPK1, APC, KRAS, PIK3CD, SOS1) of these miRNAs were predicted to be involved in endometrial cell proliferation, which suggested the potential of blastocyst secreting miRNAs as modulators of the uterine functions. However, this speculation was not verified in this study. The group also tested the CM from embryos at other developmental stages (cleavage and morula) and discovered that the analyzed miRNAs in SBCM were specific to the blastocyst stage, strengthening the point that during this particular stage the embryo may send signals to the environment in order to facilitate the subsequent implantation process.

A very recent study showed that embryos with different genders secreted different miRNAs [63]. A relatively abundant amount of miR-22, miR-122 and miR-320a were detected in CM from female bovine embryos. Taking into account that male and female embryo apply different adaptations to the external environment, they may secrete different miRNAs into the maternal environment, inducing transcriptional response of the mother to create an appropriate environment for their development.

The detection of miRNAs in the CM from pre-implantation embryos shed new light for embryo screening in the IVF process. At present, the methods used for screening embryos can be categorized as non-invasive ways and invasive ways. Non-invasive screening is mainly based on the morphological observation and metabolic profiling of the CM in order to determine the development status of embryos [64]. Although advanced technologies such as the time-lapse system have permitted keeping track of the development steps of an embryo under minimum variation of the culture environment [65], chromosomal abnormalities - which contribute to repeated failure of implantation, taking up 44.9% of morphological normal embryos [66] - cannot be ruled out. Invasive screening methods are able to identify the genomic information within the embryos. Novel technologies such as comparative genomic hybridization overcome the limitation of pre-implantation genetic screening and fluorescence in situ hybridization, promising a comprehensive analysis of chromosomes. However, the challenge of invasive screening remains regarding the damage to the embryos, and there is no definite conclusion that biopsy procedure will do no harm to the further development of embryos after they have been transferred to the uterus.

An ideal screening method should be non-invasive and accurate. Based on such consideration, miRNAs secreted by pre-implantation embryos may serve as potential biomarkers in the screening process because of their embryonic specificity, stability and easy access. However, how the secreted miRNAs are packaged might influence the judgement of embryo quality. Only one study has shown that embryonic secretion of miRNAs was carried through AGO1 [23]. None of the studies mentioned above have tested the exact release form of these extracellular miRNAs. What should be noticed is that the composition of the CM (e.g. the addition of BSA [60]) and the manipulation strategies (e.g. fertilization methods) [61, 67] have certain influence on extracellular miRNA profiles. Further investigation should clarify the forms of extracellular miRNAs within the CM in order to improve the accuracy of selection. Moreover, whether the discussed miRNAs can be used to reflect embryo viability is defined by their relative expression levels, rather than their existence, even though the latter makes them more ideal indicators. Hence, repeated experiments are required to establish measurement standards of miRNA expressions before taking them as effective biomarkers.

MiRNAs and endometrium

Intracellular miRNAs participate in uterine events during peri-implantation

Uterine sensitivity to implantation can be divided into three phases: pre-receptive phase, receptive phase, and refractory phase [38]. Implantation can only occur on the receptive phase, when the uterus is able to accept and accommodate the embryo. Collaboration of estrogen and progesterone directs the uterus into the receptive phase, accompanied by morphological and functional changes in the epithelium and the stroma [7]. Investigations of genes (such as DROSHA, DGCR8, XPO5, DICER, AGO1–4) related to miRNA synthesis and transport revealed vivid activities of miRNA production, variable miRNA expression profiles at different endometrial stages suggest the regulatory role of miRNAs in endometrial receptivity [68]. Hsa-miR-30b and hsa-miR-30d were found to be significantly upregulated and hsa-miR-494 to be downregulated in the receptive endometrium (LH + 7) compared with the pre-receptive endometrium (LH + 2) from healthy fertile women. The predicted target genes of these miRNAs were involved in cyclic remodeling of the endometrium, including endometrial maturation to the receptive state [69]. In mice, decreased expressions of miR-181 and miR-223-3p on Day 4 of pregnancy (WOI) were shown to be essential for initiating implantation [70, 71], since these miRNAs lowered the expression of LIF, a promising marker of implantation, and impeded implantation. Increased expression of miR-223-3p also reduced the formation of pinopodes, large apical protrusions that appear on the surface of epithelium and that might serve as the preferred attachment site for the embryos [71].

In preparation for embryo adhesion, the endometrial luminal epithelium must convert to an adhesion competent state to support the interactions with the embryo [5], this includes the alternations of anti-adhesive components on the endometrial luminal epithelium. Mucin 1 (Muc1) is an integral transmembrane mucin glycoprotein expressed on the apical surface of endometrial epithelia, acting as an inhibitor of embryo attachment. The expression of Muc1 in mouse decreased significantly during the implantation window, which might be regulated by miR-199a, let-7a, and let-7b. These miRNAs presented an inverse trend in the receptive endometrium [72, 73]. Type-1 insulin-like growth factor receptor (IGF1R) is up-regulated in the endometrial epithelium during the receptive stage. This increase might contribute to an adhesive interaction at the cell surface. High level of miR-145 inhibits embryo attachment partly through regulating endometrial IGF1R. This may provide an explanation for repeated implantation failure (RIF), since elevation of miR-145 has been shown in the endometrium of RIF patients [74].

During the receptive stage, the endometrial epithelium exhibits epithelial-mesenchymal transition (EMT) features, becoming less polarized and displaying remodeling of cell junctions to facilitate interaction with trophectoderm [5]. As a member of the miR-200 family who play a critical role in the suppression of EMT [75], miR-429 exhibited a declined expression during implantation in mice. Enhancement of miR-429 resulted in suppression of the migratory and invasive capacities of cells probably through targeting protocadherin 8, leading to reduced implantation sites [76]. On the contrary, miR-126-3p was specifically up-regulated in implantation sites, promoting cell migratory and invasive capacity by regulating the expression of integrin α11 [77]. Progesterone induced the expression of miR-125b in human EEC. Increased miR-125b inhibited cell movement and impeded implantation by suppressing the expression of MMP26, a member of the matrix metalloproteinase family which is involved in degradation of extracellular matrix [78].

In primates and rodents with invasive implantation, penetration of the trophoblast triggers a series of stromal response termed decidualization, which involves massive proliferation, differentiation and apoptosis of the stromal cells [4]. Some miRNAs are enhanced during decidualization. Mmu-miR-96 promoted the apoptosis of stromal and decidual cells by regulating anti-apoptotic factor Bcl-2 [79]. MiR-181a stimulated the expression of human endometrial stromal cell (hESC) decidualization-related gene (such as FOXO1A, PRL, IGFBP-1, DCN, TIMP3) and induced morphological transformation [80]. Other miRNAs are repressed during this period. MiR-222 participated in ESC differentiation by regulating ESC terminally withdrawing from the cell cycle partly through permitting CDKN1C/p57 [81]. Down-regulation of mmu-miR-200a and mmu-miR-141 facilitated the expression of PTEN, which in turn influenced cell proliferation and apoptosis during decidualization [82, 83].

Uterine luminal fluid exhibits specific extracellular miRNA profiles

Growing interests in extracellular miRNAs have led to the speculation of whether endometrium is able to secrete miRNAs. Studies have confirmed that miRNAs are encapsulated within EVs in ULF and uterine aspirates in human [84], sheep [22], and pigs [54]. Immunostaining results of membrane markers of exosomes in vivo highlighted an increased secretion trend in both luminal and glandular epithelial cells across the menstrual cycle, and the secretion reached a peak during WOI [85]. In vitro experiments compared the miRNA profiles in EEC with that in their secreted exosomes and found 13 among the 227 miRNAs were exclusively present in exosomes/microvesicles while five miRNAs were unique to EEC. The target genes of these exosome-enriched miRNAs were involved in several signaling pathways associated with implantation [86]. Another study in ewes revealed 53 commonly expressed miRNAs in ULF extracellular vesicles derived from both the cycling ewes and the pregnant ewes on Day 14, and one miRNA, bta-miR-423, was solely detected in the pregnant sample. Bta-miR-423 is thought to target genes associated with metabolism, immune system, cell cycle and apoptosis [22].

In the process of IVF, inadequate uterine receptivity is considered to be responsible for nearly 2/3 of implantation failures [87]. Current methods used for the endometrial receptivity evaluation is based on morphological assessment and genome investigation. Large number of molecules have been proposed as receptive biomarkers, however, these markers sometimes present differences among individuals which bring misleading judgments on the fertility status [88]. The detection of extracellular miRNAs in ULF bring new options for the non-invasive diagnosis of endometrial receptivity, but more investigations need to be involved before it become a real approach in clinical practice.

MiRNAs in embryo-maternal interaction

Synchronized development between the embryo and the endometrium is essential for successful implantation, and embryo-endometrial asynchrony beyond a certain time period leads to declined implantation rate [89]. To ensure synchronization, conversation between embryo and the uterus must hold. Besides the regulation of estrogen and progesterone, both the embryo and the endometrium can secrete unique signals to inform the other party, adjusting the pace of their development. For example, the embryo releases pregnancy recognition signals (e.g. chorionic gonadotropin for human, interferon tau for ruminants) to prevent luteolysis by prostaglandin F2α in order to maintain a mild environment for pregnancy, while uterine secretions regulate the embryo development status and promote trophectoderm proliferation, migration, as well as attachment to the endometrial luminal epithelium.

There is a growing interest in studying the microenvironment where bidirectional communication takes place. Within the uterine cavity, ULF - secreted by luminal and glandular epithelia and in intimate contact with the embryo and endometrial epithelium - is considered to be essential for embryo development and implantation [90, 91]. The secretion profiles of the ULF are believed to reflect the receptive state of the endometrium, thus ULF has been proposed to serve as a source of non-invasion biomarkers.

MiRNAs, contained within exosomes/microvesicles, have been detected in ULF and uterine aspirates among species. It was suggested that they might have a role in embryo-maternal interactions during implantation (Fig. 1). Vilella et al. [85] demonstrated a variable expression pattern of miRNAs in human endometrial fluid secreted by the endometrial glands at different stages of the menstrual cycles. The group compared the WOI with the rest of the menstrual cycle and discovered that hsa-miR-30d was the most differently expressed miRNA. Further investigation revealed that this unique miRNA could be transported through exosomes. By using an in vitro mouse model, miR-30d carried through exosomes was shown to be internalized by mouse blastocysts and modified the embryonic transcriptome and phenotype. Supplement of mimic miR-30d to the embryo led to overexpression of ten genes (such as ITGB3, ITGA7 and CDH5) which are related to cell adhesion, integrin-mediated signaling pathways and developmental maturation. The adhesion rate of embryo was also improved.

In another study, Cuman et al. [23] provided more direct evidence that miRNA secreted by the embryo participates in modulating uterine functions. CM from human blastocysts with opposite implantation outcomes were analyzed, and the concentration of miR-661 was reported to be significantly higher in the CM collected from blastocysts that failed to implant than those who implanted successfully. The group later used CM instead of supplement of miRNA to show that the enhanced level of miR-661 in the extracellular environment elevated the intracellular expression of miR-661 in cultured human EEC. Further investigation unraveled that miR-661 was transported by AGO1 and taken up by human EEC. Elevated miR-661 expression inhibited the attachment of trophoblast cell line spheroid to human EEC, partly via PVRL1, a membrane-bound immunoglobulin-like cell adhesion molecule.

These studies show that both the embryo and the uterus can secrete specific miRNAs according to their own conditions, and these secreted miRNAs are likely to be taken up by the other party to modify the transcriptomes in them to facilitate implantation.

Circulating miRNAs and pregnancy

Circulating miRNAs refer to cell-free miRNAs which are present in peripheral blood [92]. Many studies show circulating miRNAs as promising biomarkers for the diagnosis and prognosis of several cancers [93]. There is certain evidence that circulating miRNAs have indicative functions in the process of pregnancy. Placenta-specific miRNAs, mainly linked to the chromosome 19 miRNA cluster, are widely expressed in the blood plasma of pregnant women [94, 95]. These miRNAs (e.g. miR-515-3p, miR-517a, miR-517c, miR-518b, miR-526b, and miR-323-3p) are probably released by the trophoblast cell into the maternal circulation system through exosomes during pregnancy, and their presence is rapidly cleared after parturition [96]. Other studies highlight that miRNAs are possible indicators for pregnancy failure and complications. Patients with ectopic pregnancy (EP) or spontaneous abortion (SA) were reported to carry a significantly lower serum concentration of miR-517a, miR-519d, and miR-525-3p compared with women with viable intrauterine pregnancy; a unique high expression of serum miR-323-3p was found in the EP group, which helps to distinguish EP and SA, showing potential of being a biomarker [97].

Only few studies aimed to investigate the correlation between circulating miRNAs and embryo implantation. Kresowik et al. [98] screened the expression of several miRNAs in the endometrial tissue and serum of fertile women and discovered that miR-31 was significantly up-regulated in serum during the WOI, which was consistent with its expression in tissue. In vitro experiments suggested that this remarkable increase was associated with the rise of progesterone level. Immune related genes such as FOXP3 and CXCL12 were significantly downregulated in the endometrial tissue due to the increase of miR-31, suggesting this miRNA plays a role in regulating the immune system during implantation. Ioannidis et al. [99] profiled plasma miRNAs from pregnant and non-pregnant heifers and discovered that the concentration of miR-26 was higher in pregnant heifers on Day 16 of pregnancy and the level of this miRNA increased from Day 16 to Day 24. Considering the onset of implantation in cattle is around Day 19 after fertilization [2], miR-26 might be a candidate biomarker for very early pregnancy in cows. Another study in cows revealed that circulating EV-derived miRNA is not only able to identify pregnancy, but is able to distinguish between successful implantation and embryonic mortality at the early stage of pregnancy [100]. The expression of miR-25, miR-16a/b, and miR-3596 at day 17 was higher in the embryo mortality group compared to both the pregnant and control groups, suggesting their potentials in differentiating pregnancy status. Differentially expressed miRNAs were also confirmed in serum exosomes collected from pregnant and non-pregnant mares, showing potential role in maternal recognition of pregnancy probably through regulating the focal adhesion pathway [101].

Circulating miRNAs have been suggested to be effective biomarkers due to their stability, informativeness and non-invasive detection. However, defining the existence form of circulating miRNAs is necessary. Many studies are conducted on EV-derived miRNAs, though this form of miRNA accounts for only a small fraction of the total extracellular miRNAs [29]. Whether other forms of extracellular miRNAs have indicative functions remains to be studied. Moreover, the result of circulating miRNAs studies can be affected by experimental and analytical method [102]. Further effort applying standardized and consistent method will be required to determine whether circulating miRNAs can be used as reliable biomarkers for implantation events, especially for detecting endometrial receptivity.

Conclusions

Implantation is an elaborate process requiring the synchronous development of a viable embryo and a receptive endometrium. MiRNA works as a regulator of gene expression and is actively involved in regulating embryo development, endometrial functions, and embryo-maternal communications. The verification of functional extracellular miRNAs brings new opportunities for improving implantation outcomes mainly from two aspects: first, intercellular communication through extracellular miRNAs provides a new dimension for understanding the mechanism of implantation; second, extracellular miRNAs have the potential for being effective biomarkers in IVF-ET for detection and prognosis of embryo quality and endometrium receptivity.

In view of the pleiotropic effects of miRNAs, it is difficult to define the specific role of a particular miRNA. At present, most of the miRNA experiments are conducted on cellular level in vitro, but some groups also apply in vivo models by injecting miRNA mimics and (or) inhibitors. Indeed, the supplement of miRNA (or its inhibitor) will lead to expressional changes on the specific predicted target gene, which causes phenotypic changes in turn. However, it can not be excluded the possible effect of other potential target genes which might be regulated by the same miRNA. Since current experiments only provide limited potential of specific miRNAs, further investigations and more data are required to summarize the rule of miRNA regulation. In contrast, miRNAs, especially extracellular miRNAs, present a brighter future for developing non-invasive biomarkers. Besides the conservativeness, extracellular miRNAs are highly stable and sensitive in bio-environment. Meanwhile, they present specificity associated with physiological and pathological conditions. Non-invasive access is another striking advantage of extracellular miRNAs. However, it is necessary to define the package forms and secretion mechanisms of extracellular miRNAs, since this may influence our judgement on its function as well as the accuracy of evaluation when applying one as biomarker for certain conditions.

The exploration of relationship between extracellular miRNAs and implantation had only begun. More research should be done and their results should be replicated in clinical trials in order to bring true efficiency to implantation improvement.

Abbreviations

AGO: 

Argonaute

ART: 

Assisted reproductive technology

CM: 

Culture media

EEC: 

Endometrial epithelium cells

EMT: 

Epithelial-mesenchymal transition

EP: 

Ectopic pregnancy

EV: 

Extracellular vesicles

FAM: 

Focal adhesion molecules

hESC: 

Human endometrial stromal cell

IGF1R: 

Type-1 insulin-like growth factor receptor

IVF: 

In vitro fertilization

RIF: 

Repeated implantation failure

RISC: 

RNA-induced silencing complex

SA: 

Spontaneous abortion

SBCM: 

Spent blastocyst culture media

ULF: 

Uterine luminal fluid

WOI: 

Window of implantation

XPO5: 

Exportin 5

ZGA: 

Zygote genome activation

Declarations

Acknowledgements

Not applicable.

Funding

This study was supported by the science and technology projects of the Zhejiang province (Grant Agreement No.: 2015C32024, 2016C02054-8, [2013]215-50).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors’ contributions

JJL and SYW were involved in data acquisition, analysis and manuscript drifting. JJL was the major contributor in writing the manuscript. ZGW approved the final manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
College of Animal Sciences, Zhejiang University

References

  1. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345(19):1400–8.View ArticlePubMedGoogle Scholar
  2. Bauersachs S, Wolf E. Uterine responses to the preattachment embryo in domestic ungulates: recognition of pregnancy and preparation for implantation. Annu Rev Anim Biosci. 2015;3:489–511.View ArticlePubMedGoogle Scholar
  3. Walsh SW, Williams EJ, Evans ACA. Review of the causes of poor fertility in high milk producing dairy cows. Anim Reprod Sci. 2011;123(3–4):127–38.View ArticlePubMedGoogle Scholar
  4. Bazer FW, Spencer TE, Johnson GA, Burghardt RC. Uterine receptivity to implantation of blastocysts in mammals. Front Biosci (Schol Ed). 2011;3:745–67.View ArticleGoogle Scholar
  5. Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, et al. Embryo implantation. Dev Biol. 2000;223(2):217–37.View ArticlePubMedGoogle Scholar
  6. Sharkey AM, Macklon NS. The science of implantation emerges blinking into the light. Reprod BioMed Online. 2013;27(5):453–60.View ArticlePubMedGoogle Scholar
  7. Zhang S, Lin H, Kong S, Wang S, Wang H, Wang H, et al. Physiological and molecular determinants of embryo implantation. Mol Asp Med. 2013;34(5):939–80.View ArticleGoogle Scholar
  8. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.View ArticlePubMedGoogle Scholar
  9. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15(8):509–24.View ArticlePubMedGoogle Scholar
  10. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513–8.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56(11):1733–41.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Kosaka N, Iguchi H, Ochiya T. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010;101(10):2087–92.View ArticlePubMedGoogle Scholar
  13. Xu L, Yang BF, Ai J. MicroRNA transport: a new way in cell communication. J Cell Physiol. 2013;228(8):1713–9.View ArticlePubMedGoogle Scholar
  14. Rayner KJ, Hennessy EJ. Extracellular communication via microRNA: lipid particles have a new message. J Lipid Res. 2013;54(5):1174–81.View ArticlePubMedPubMed CentralGoogle Scholar
  15. Tesfaye D, Salilew-Wondim D, Gebremedhn S, Sohel MM, Pandey HO, Hoelker M, et al. Potential role of microRNAs in mammalian female fertility. Reprod Fertil Dev. 2016;29(1):8–23.View ArticlePubMedGoogle Scholar
  16. Teague EM, Print CG, Hull ML. The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update. 2010;16(2):142–65.View ArticlePubMedGoogle Scholar
  17. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997–1006.View ArticlePubMedGoogle Scholar
  18. Kosaka N, Izumi H, Sekine K, Ochiya T. MicroRNA as a new immune-regulatory agent in breast milk. Silence. 2010;1(1):7.View ArticlePubMedPubMed CentralGoogle Scholar
  19. Momen-Heravi F, Trachtenberg AJ, Kuo WP, Cheng YS. Genomewide study of salivary microRNAs for detection of oral cancer. J Dent Res. 2014;93(7 Suppl):86S–93S.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Hanke M, Hoefig K, Merz H, Feller AC, Kausch I, Jocham D, et al. A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol Oncol. 2010;28(6):655–61.View ArticlePubMedGoogle Scholar
  21. Vojtech L, Woo S, Hughes S, Levy C, Ballweber L, Sauteraud RP, et al. Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic Acids Res. 2014;42(11):7290–304.View ArticlePubMedPubMed CentralGoogle Scholar
  22. Burns G, Brooks K, Wildung M, Navakanitworakul R, Christenson LK, Spencer TE. Extracellular vesicles in luminal fluid of the ovine uterus. PLoS One. 2014;9(3):e90913.View ArticlePubMedPubMed CentralGoogle Scholar
  23. Cuman C, Van Sinderen M, Gantier MP, Rainczuk K, Sorby K, Rombauts L, et al. Human blastocyst secreted microRNA regulate endometrial epithelial cell adhesion. EBioMedicine. 2015;2(10):1528–35.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Wang K, Zhang S, Weber J, Baxter D, Galas DJ. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res. 2010;38(20):7248–59.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Tabet F, Vickers KC, Cuesta TL, Wiese CB, Shoucri BM, Lambert G, et al. HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells. Nat Commun. 2014;5:3292.View ArticlePubMedPubMed CentralGoogle Scholar
  26. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2009;2(100):ra81.Google Scholar
  27. Maida Y, Takakura M, Nishiuchi T, Yoshimoto T, Kyo S. Exosomal transfer of functional small RNAs mediates cancer-stroma communication in human endometrium. Cancer Med. 2016;5(2):304–14.View ArticlePubMedGoogle Scholar
  28. Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 2011;39(16):7223–33.View ArticlePubMedPubMed CentralGoogle Scholar
  29. Turchinovich A, Weiz L, Burwinkel B. Extracellular miRNAs: the mystery of their origin and function. Trends Biochem Sci. 2012;37(11):460–5.View ArticlePubMedGoogle Scholar
  30. Machtinger R, Laurent LC, Baccarelli AA. Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation. Hum Reprod Update. 2016;22(2):182–93.PubMedGoogle Scholar
  31. Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.View ArticlePubMedGoogle Scholar
  32. Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z, et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell. 2010;39(1):133–44.View ArticlePubMedGoogle Scholar
  33. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013;91(4):431–7.View ArticleGoogle Scholar
  34. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013;32(3–4):623–42.View ArticlePubMedGoogle Scholar
  35. Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164(6):1226–32.View ArticlePubMedGoogle Scholar
  36. Murray MJ, Lessey BA. Embryo implantation and tumor metastasis: common pathways of invasion and angiogenesis. Semin Reprod Endocrinol. 1999;17(3):275–90.View ArticlePubMedGoogle Scholar
  37. Greening DW, Nguyen HP, Elgass K, Simpson RJ, Salamonsen LA. Human endometrial exosomes contain hormone-specific cargo modulating trophoblast adhesive capacity: insights into endometrial-embryo interactions. Biol Reprod. 2016;94(2):38.View ArticlePubMedGoogle Scholar
  38. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7(3):185–99.View ArticlePubMedGoogle Scholar
  39. Klein C. Pregnancy recognition and implantation of the conceptus in the mare. Adv Anat Embryol Cell Biol. 2015;216:165–88.View ArticlePubMedGoogle Scholar
  40. Prather RS. First NL. A review of early mouse embryogenesis and its applications to domestic species. J Anim Sci. 1988;66(10):2626–35.View ArticlePubMedGoogle Scholar
  41. Yang Y, Bai W, Zhang L, Yin G, Wang X, Wang J, et al. Determination of microRNAs in mouse preimplantation embryos by microarray. Dev Dyn. 2008;237(9):2315–27.View ArticlePubMedGoogle Scholar
  42. Suh N, Baehner L, Moltzahn F, Melton C, Shenoy A, Chen J, et al. MicroRNA function is globally suppressed in mouse oocytes and early embryos. Curr Biol. 2010;20(3):271–7.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Yang Q, Lin J, Liu M, Li R, Tian B, Zhang X, et al. Highly sensitive sequencing reveals dynamic modifications and activities of small RNAs in mouse oocytes and early embryos. Sci Adv. 2016;2(6):e1501482.View ArticlePubMedPubMed CentralGoogle Scholar
  44. Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, et al. Dicer is essential for mouse development. Nat Genet. 2003;35(3):215–7.View ArticlePubMedGoogle Scholar
  45. Alisch RS, Jin P, Epstein M, Caspary T, Warren ST. Argonaute2 is essential for mammalian gastrulation and proper mesoderm formation. PLoS Genet. 2007;3(12):e227.View ArticlePubMedPubMed CentralGoogle Scholar
  46. Pernaute B, Spruce T, Rodriguez TA, Manzanares M. MiRNA-mediated regulation of cell signaling and homeostasis in the early mouse embryo. Cell Cycle. 2011;10(4):584–91.View ArticlePubMedGoogle Scholar
  47. Zhang J, Wang Y, Liu X, Jiang S, Zhao C, Shen R, et al. Expression and potential role of microRNA-29b in mouse early embryo development. Cell Physiol Biochem. 2015;35(3):1178–87.View ArticlePubMedGoogle Scholar
  48. Sinha PB, Tesfaye D, Rings F, Hossien M, Hoelker M, Held E, et al. MicroRNA-130b is involved in bovine granulosa and cumulus cells function, oocyte maturation and blastocyst formation. J Ovarian Res. 2017;10(1):37.View ArticlePubMedPubMed CentralGoogle Scholar
  49. Viswanathan SR, Mermel CH, Lu J, CW L, Golub TR, Daley GQ. MicroRNA expression during trophectoderm specification. PLoS One. 2009;4(7):e6143.View ArticlePubMedPubMed CentralGoogle Scholar
  50. Xie L, Mouillet JF, Chu T, Parks WT, Sadovsky E, Knofler M, et al. C19MC microRNAs regulate the migration of human trophoblasts. Endocrinology. 2014;155(12):4975–85.View ArticlePubMedPubMed CentralGoogle Scholar
  51. Dai Y, Qiu Z, Diao Z, Shen L, Xue P, Sun H, et al. MicroRNA-155 inhibits proliferation and migration of human extravillous trophoblast derived HTR-8/SVneo cells via down-regulating cyclin D1. Placenta. 2012;33(10):824–9.View ArticlePubMedGoogle Scholar
  52. Fu G, Ye G, Nadeem L, Ji L, Manchanda T, Wang Y, et al. MicroRNA-376c impairs transforming growth factor-beta and nodal signaling to promote trophoblast cell proliferation and invasion. Hypertension. 2013;61(4):864–72.View ArticlePubMedGoogle Scholar
  53. Luo L, Ye G, Nadeem L, Fu G, Yang BB, Honarparvar E, et al. MicroRNA-378a-5p promotes trophoblast cell survival, migration and invasion by targeting nodal. J Cell Sci. 2012;125(Pt 13):3124–32.View ArticlePubMedGoogle Scholar
  54. Krawczynski K, Najmula J, Bauersachs S, Kaczmarek MM. MicroRNAome of porcine conceptuses and trophoblasts: expression profile of micrornas and their potential to regulate genes crucial for establishment of pregnancy. Biol Reprod. 2015;92(1):21.View ArticlePubMedGoogle Scholar
  55. Liu WM, Pang RT, Cheong AW, Ng EH, Lao K, Lee KF, et al. Involvement of microRNA lethal-7a in the regulation of embryo implantation in mice. PLoS One. 2012;7(5):e37039.View ArticlePubMedPubMed CentralGoogle Scholar
  56. Cheong AW, Pang RT, Liu WM, Kottawatta KS, Lee KF, Yeung WS. MicroRNA let-7a and dicer are important in the activation and implantation of delayed implanting mouse embryos. Hum Reprod. 2014;29(4):750–62.View ArticlePubMedGoogle Scholar
  57. Stowe HM, Curry E, Calcatera SM, Krisher RL, Paczkowski M, Pratt SL. Cloning and expression of porcine dicer and the impact of developmental stage and culture conditions on MicroRNA expression in porcine embryos. Gene. 2012;501(2):198–205.View ArticlePubMedGoogle Scholar
  58. Kropp J, Khatib H. Characterization of microRNA in bovine in vitro culture media associated with embryo quality and development. J Dairy Sci. 2015;98(9):6552–63.View ArticlePubMedGoogle Scholar
  59. Tan K, Wang X, Zhang Z, Miao K, Yu Y, An L, et al. Downregulation of miR-199a-5p disrupts the developmental potential of in vitro-fertilized mouse blastocysts. Biol Reprod. 2016;95(3):54.View ArticlePubMedGoogle Scholar
  60. Kropp J, Salih SM, Khatib H. Expression of microRNAs in bovine and human pre-implantation embryo culture media. Front Genet. 2014;5:91.View ArticlePubMedPubMed CentralGoogle Scholar
  61. Rosenbluth EM, Shelton DN, Wells LM. Sparks AE, van Voorhis BJ. Human embryos secrete microRNAs into culture media--a potential biomarker for implantation. Fertil Steril. 2014;101(5):1493–500.View ArticlePubMedGoogle Scholar
  62. Capalbo A, Ubaldi FM, Cimadomo D, Noli L, Khalaf Y, Farcomeni A, et al. MicroRNAs in spent blastocyst culture medium are derived from trophectoderm cells and can be explored for human embryo reproductive competence assessment. Fertil Steril 2016;105(1):225–235e1–3.Google Scholar
  63. Gross N, Kropp J, Khatib H. Sexual dimorphism of miRNAs secreted by bovine in vitro-produced embryos. Front Genet. 2017;8:39.View ArticlePubMedPubMed CentralGoogle Scholar
  64. Das M, Holzer HE. Recurrent implantation failure: gamete and embryo factors. Fertil Steril. 2012;97(5):1021–7.View ArticlePubMedGoogle Scholar
  65. Aparicio B, Cruz M, Meseguer MI. Morphokinetic analysis the answer? Reprod BioMed Online. 2013;27(6):654–63.View ArticlePubMedGoogle Scholar
  66. Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012;5(1):24.View ArticlePubMedPubMed CentralGoogle Scholar
  67. Noli L, Capalbo A, Dajani Y, Cimadomo D, Bvumbe J, Rienzi L, et al. Human embryos created by embryo splitting secrete significantly lower levels of miRNA-30c. Stem Cells Dev. 2016;25(24):1853–62.View ArticlePubMedGoogle Scholar
  68. Krawczynski K, Bauersachs S, Reliszko ZP, Graf A, Kaczmarek MM. Expression of microRNAs and isomiRs in the porcine endometrium: implications for gene regulation at the maternal-conceptus interface. BMC Genomics. 2015;16:906.View ArticlePubMedPubMed CentralGoogle Scholar
  69. Altmae S, Martinez-Conejero JA, Esteban FJ, Ruiz-Alonso M, Stavreus-Evers A, Horcajadas JA, et al. MicroRNAs miR-30b, miR-30d, and miR-494 regulate human endometrial receptivity. Reprod Sci. 2013;20(3):308–17.View ArticlePubMedPubMed CentralGoogle Scholar
  70. Chu B, Zhong L, Dou S, Wang J, Li J, Wang M, Shi Q, Mei Y, Wu M. miRNA-181 regulates embryo implantation in mice through targeting leukemia inhibitory factor. J Mol Cell Biol. 2015;7(1):12–22.View ArticlePubMedGoogle Scholar
  71. Dong X, Sui C, Huang K, Wang L, Hu D, Xiong T, et al. MicroRNA-223-3p suppresses leukemia inhibitory factor expression and pinopodes formation during embryo implantation in mice. Am J Transl Res. 2016;8(2):1155–63.PubMedPubMed CentralGoogle Scholar
  72. Inyawilert W, TY F, Lin CT, Tang PC. Let-7-mediated suppression of mucin 1 expression in the mouse uterus during embryo implantation. J Reprod Dev. 2015;61(2):138–44.View ArticlePubMedPubMed CentralGoogle Scholar
  73. Inyawilert W, TY F, Lin CT, Tang PC. MicroRNA-199a mediates mucin 1 expression in mouse uterus during implantation. Reprod Fertil Dev. 2014;26(5):653–64.View ArticlePubMedGoogle Scholar
  74. Kang YJ, Lees M, Matthews LC, Kimber SJ, Forbes K, Aplin JD. MiR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R. J Cell Sci. 2015;128(4):804–14.View ArticlePubMedGoogle Scholar
  75. Mongroo PS, Rustgi AK. The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Biol Ther. 2010;10(3):219–22.View ArticlePubMedPubMed CentralGoogle Scholar
  76. Li Z, Gou J, Jia J, Zhao X. MicroRNA-429 functions as a regulator of epithelial-mesenchymal transition by targeting Pcdh8 during murine embryo implantation. Hum Reprod. 2015;30(3):507–18.View ArticlePubMedGoogle Scholar
  77. Li Z, Jia J, Gou J, Tong A, Liu X, Zhao X, et al. Mmu-miR-126a-3p plays a role in murine embryo implantation by regulating Itga11. Reprod BioMed Online. 2015;31(3):384–93.View ArticlePubMedGoogle Scholar
  78. Chen C, Zhao Y, Yu Y, Li R, Qiao J. MiR-125b regulates endometrial receptivity by targeting MMP26 in women undergoing IVF-ET with elevated progesterone on HCG priming day. Sci Rep. 2016;6:25302.View ArticlePubMedPubMed CentralGoogle Scholar
  79. Yang Y, Xie Y, Wu M, Geng Y, Li R, Xu L, et al. Expression of mmu-miR-96 in the endometrium during early pregnancy and its regulatory effects on stromal cell apoptosis via Bcl2. Mol Med Rep. 2017;15(4):1547–54.View ArticlePubMedPubMed CentralGoogle Scholar
  80. Zhang Q, Zhang H, Jiang Y, Xue B, Diao Z, Ding L, et al. MicroRNA-181a is involved in the regulation of human endometrial stromal cell decidualization by inhibiting Kruppel-like factor 12. Reprod Biol Endocrinol. 2015;13:23.View ArticlePubMedPubMed CentralGoogle Scholar
  81. Qian K, Hu L, Chen H, Li H, Liu N, Li Y, et al. Hsa-miR-222 is involved in differentiation of endometrial stromal cells in vitro. Endocrinology. 2009;150(10):4734–43.View ArticlePubMedGoogle Scholar
  82. Shen LJ, He JL, Yang DH, Ding YB, Chen XM, Geng YQ, et al. Mmu-microRNA-200a overexpression leads to implantation defect by targeting phosphatase and tensin homolog in mouse uterus. Reprod Sci. 2013;20(12):1518–28.View ArticlePubMedPubMed CentralGoogle Scholar
  83. Liu X, Gao R, Chen X, Zhang H, Zheng A, Yang D, et al. Possible roles of mmu-miR-141 in the endometrium of mice in early pregnancy following embryo implantation. PLoS One. 2013;8(6):e67382.View ArticlePubMedPubMed CentralGoogle Scholar
  84. Campoy I, Lanau L, Altadill T, Sequeiros T, Cabrera S, Cubo-Abert M, et al. Exosome-like vesicles in uterine aspirates: a comparison of ultracentrifugation-based isolation protocols. J Transl Med. 2016;14(1):180.View ArticlePubMedPubMed CentralGoogle Scholar
  85. Vilella F, Moreno-Moya JM, Balaguer N, Grasso A, Herrero M, Martinez S, et al. Hsa-miR-30d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might modify its transcriptome. Development. 2015;142(18):3210–21.View ArticlePubMedGoogle Scholar
  86. Ng YH, Rome S, Jalabert A, Forterre A, Singh H, Hincks CL, et al. Endometrial exosomes/microvesicles in the uterine microenvironment: a new paradigm for embryo-endometrial cross talk at implantation. PLoS One. 2013;8(3):e58502.View ArticlePubMedPubMed CentralGoogle Scholar
  87. Melford SE, Taylor AH, Konje JC. Of mice and (wo)men: factors influencing successful implantation including endocannabinoids. Hum Reprod Update. 2014;20(3):415–28.View ArticlePubMedGoogle Scholar
  88. Coutifaris C, Myers ER, Guzick DS, Diamond MP, Carson SA, Legro RS, et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril. 2004;82(5):1264–72.View ArticlePubMedGoogle Scholar
  89. Teh WT, McBain J, Rogers P. What is the contribution of embryo-endometrial asynchrony to implantation failure? J Assist Reprod Genet. 2016;33(11):1419–30.View ArticlePubMedPubMed CentralGoogle Scholar
  90. Salamonsen LA, Evans J, Nguyen HP, Edgell TA. The microenvironment of human implantation: determinant of reproductive success. Am J Reprod Immunol. 2016;75(3):218–25.View ArticlePubMedGoogle Scholar
  91. Berlanga O, Bradshaw HB, Vilella-Mitjana F, Garrido-Gomez T, Simon C. How endometrial secretomics can help in predicting implantation. Placenta. 2011;32(Suppl 3):S271–5.View ArticlePubMedGoogle Scholar
  92. Ortiz-Quintero B. Cell-free microRNAs in blood and other body fluids, as cancer biomarkers. Cell Prolif. 2016;49(3):281–303.View ArticlePubMedGoogle Scholar
  93. Bertoli G, Cava C, Castiglioni I. MicroRNAs: new biomarkers for diagnosis, prognosis, therapy prediction and therapeutic tools for breast cancer. Theranostics. 2015;5(10):1122–43.View ArticlePubMedPubMed CentralGoogle Scholar
  94. Luo SS, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, et al. Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod. 2009;81(4):717–29.View ArticlePubMedGoogle Scholar
  95. Donker RB, Mouillet JF, Chu T, Hubel CA, Stolz DB, Morelli AE, et al. The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes. Mol Hum Reprod. 2012;18(8):417–24.View ArticlePubMedPubMed CentralGoogle Scholar
  96. Miura K, Miura S, Yamasaki K, Higashijima A, Kinoshita A, Yoshiura K, et al. Identification of pregnancy-associated microRNAs in maternal plasma. Clin Chem. 2010;56(11):1767–71.View ArticlePubMedGoogle Scholar
  97. Zhao Z, Zhao Q, Warrick J, Lockwood CM, Woodworth A, Moley KH, et al. Circulating microRNA miR-323-3p as a biomarker of ectopic pregnancy. Clin Chem. 2012;58(5):896–905.View ArticlePubMedPubMed CentralGoogle Scholar
  98. Kresowik JD, Devor EJ, Van Voorhis BJ, Leslie KK. MicroRNA-31 is significantly elevated in both human endometrium and serum during the window of implantation: a potential biomarker for optimum receptivity. Biol Reprod. 2014;91(1):17.View ArticlePubMedGoogle Scholar
  99. Ioannidis J, Donadeu FX. Circulating miRNA signatures of early pregnancy in cattle. BMC Genomics. 2016;17:184.View ArticlePubMedPubMed CentralGoogle Scholar
  100. Pohler KG, Green JA, Moley LA, Gunewardena S, Hung WT, Payton RR, Hong X, Christenson LK, Geary TW, Smith MF. Circulating microRNA as candidates for early embryonic viability in cattle. Mol Reprod Dev. 2017;84(8):731–43.View ArticlePubMedGoogle Scholar
  101. Klohonatz KM, Cameron AD, Hergenreder JR, Da SJ, Belk AD, Veeramachaneni DN, et al. Circulating miRNAs as potential alternative cell signaling associated with maternal recognition of pregnancy in the mare. Biol Reprod. 2016;95(6):124.View ArticlePubMedGoogle Scholar
  102. Tiberio P, Callari M, Angeloni V, Daidone MG, Appierto V. Challenges in using circulating miRNAs as cancer biomarkers. Biomed Res Int. 2015;2015:731479.View ArticlePubMedPubMed CentralGoogle Scholar

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