Mir-661: A key Factor in Embryo-Maternal dialog With Potential Clinical Application to Predict Implantation Outcome?

Implantation resulting in a full-term pregnancy is, by large, more than a passive process in which the developed conceptus is passively glued to the uterus through adhesive molecules. It is the result of a perfectly orchestrated dialog between a viable embryo and a receptive endometrium, through a mixture of paracrine and juxtacrine processes in which many key proteins and growth factors play fundamental roles (Pellicer et al., 2002.) Since their discovery, microRNAs have become prominent regulatory candidates, providing missing links for a few biological pathways in this process, although their exact role in human normal embryo formation and endometrial preparation for pregnancy remains unclear (Galliano and Pellicer, 2014). Very recently it was shown, that human endometrium delivers miRNA messages “bottled” in protective structures such us exosomes (Ng et al., 2013) to exert a biological function in the recipient embryo (Balaguer et al., 2015). In this issue, Cuman et al (Cuman et al., 2015) show that miRNA also travel in the opposite way: secreted by the embryo to alter endometrial epithelial adhesion. More specifically, authors show that miR-661 can be found to be differentially over-represented in culture media of embryos which failed to implant. Subsequently they show that mir661 is taken up by primary human endometrial epithelial cells (HEEC) inducing the inhibition of nectin 1 (a protein mediating cell adhesion) in endometrial cells and this results in reduced attachment of trophoblast cell line spheroids to HEEC. Provided that in-silico analysis showed other potential proteins to be regulated by mir661 it would not be surprising to uncover in the near future complimentary mechanisms through which this miRNA regulates embryo-maternal adhesion. Anyhow, observations in this work highlight the importance of miRNA molecules secreted by the embryo in initiating the event of implantation.

Selection of the best embryo for transfer is imprecise and the current methods involve morphologic criteria (Cruz et al., 2011), on the belief that those with a better shape are more likely to be chromosomically normal and implant. However, many morphologically normal blastocysts are aneuploid or will not implant (Fragouli et al., 2011) whilst embryos with an abnormal chromosomal content are able to do so. With the development of transcriptomics and massive sequence analysis it might be hypothetically possible to detect most of the genetic anomalies in an embryo trough pre-implantation genetic screening (PGS). However such approach is invasive, expensive, and requires embryo biopsy (Winand et al., 2014). Therefore in a world where the number of IVF cycles increase every year, there is a growing clinical interest in understanding embryo-maternal interactions to identify biomarkers of embryo quality. The purpose is obvious: to increase the pregnancy rates per transfer and reduce the presence of anomalies in them. These biomarkers are expected to allow noninvasive analysis, be stable over time, specific to embryos, and easily measured. Due to the fact that miRNAs accomplish these requirements, one might envision that the expression levels of miR661 identified by Dimiatriadis and colleagues in non-implanted blastocysts could be employed in the future in order to screen and select for good quality embryos suitable for subsequent uterine transfer.

Unfortunately, we have to lower our expectation in this regard just now, as Cuman et al study was not intended to test the predictive value of biomarkers identified during the exploratory process. Despite the fact that the authors confirmed the overrepresentation of mir661 in a separate cohort of individual non-implanting blastocysts, the number of specimens analyzed was small. Moreover the experiment was not designed to uncover the characteristics of non-implanted embryos. In these regard, factors such as ploidy or genetic abnormalities were not determined; indicators of low metabolic energy (Diez-Juan et al., 2015) or embryo damage induced during ICSI (Rosenbluth et al., 2014) were not estimated, and overall the contribution of several other factors known to affect embryo outcome and its miRNA profile (Galliano and Pellicer, 2014) were not assessed. So the question remaining is what population of non-implanted embryos overexpresses mir661? In other words, does mir661 universally indicate embryos fated to fail in implantation or just a very narrow and specific portion of them? As this question remains unanswered, the repercussions in terms of clinical usefulness of mir661 cannot currently be estimated.

This does not mean that we should neglect the potential of miR661 as a biomarker of embryo quality. It just means that further studies should be performed to identify which specific aberrant and abnormal embryo populations can be recognized by mir661 overexpression. Subsequently larger double-blinded studies with an appropriate N should be performed to test the accuracy of this marker as a predictor of implantation outcome. As the title of this comment reflects, findings provided by Cuman et al. in the context of embryo-maternal are of outstanding scientific interest. The repercussions these observations have in the clinical context however might suppose a major breakthrough and therefore well worth the effort in pursuing.

Conflict of Interest

The authors declare no conflicts of interest.