Role of microRNAs in embryo implantation

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: Endometrial receptivity; Extracellular vesicle; Implantation; MicroRNA; Viable embryo.

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)