Trophoblast derived extracellular vesicles specifically alter the transcriptome of endometrial cells and may constitute a critical component of embryo-maternal communication

• Published in: Reproductive biology and endocrinology 2021-07, Vol.19 (1), p.115-115, Article 115
• Main Authors: Godakumara, Kasun, Ord, James, Lättekivi, Freddy, Dissanayake, Keerthie, Viil, Janeli, Boggavarapu, Nageswara Rao, Faridani, Omid R, Jääger, Kersti, Velthut-Meikas, Agne, Jaakma, Ülle, Salumets, Andres, Fazeli, Alireza
• Format: Article
• Language: English
• Subjects: Analysis; Cell interactions; Cell Line, Tumor; Communication; DNA polymerase; Embryo; Embryo Implantation - physiology; Embryo, Mammalian - cytology; Embryo, Mammalian - physiology; Embryo-maternal communication; Embryonic development; Embryos; Endometrium; Endometrium - cytology; Endometrium - physiology; Extracellular matrix; Extracellular vesicles; Female; G protein-coupled receptors; G proteins; Gene expression; Gene set enrichment analysis; Gene silencing; Genetic engineering; Genetic testing; HEK293 Cells; Human reproduction; Humans; Hypotheses; Lipid bilayers; Medicin och hälsovetenskap; Membrane lipids; MicroRNA; miRNA; miRNA signalling; Physiology; Placental Circulation - physiology; Pregnancy; RNA sequencing; Transcriptome - physiology; Transcriptomes; Transcriptomics; Trophoblasts - physiology
• ISSN: 1477-7827; 1477-7827
• DOI: 10.1186/s12958-021-00801-5

The period of time when the embryo and the endometrium undergo significant morphological alterations to facilitate a successful implantation-known as "window of implantation"-is a critical moment in human reproduction. Embryo and the endometrium communicate extensively during this period, and lipid bilayer bound nanoscale extracellular vesicles (EVs) are purported to be integral to this communication. To investigate the nature of the EV-mediated embryo-maternal communication, we have supplemented trophoblast analogue spheroid (JAr) derived EVs to an endometrial analogue (RL 95-2) cell layer and characterized the transcriptomic alterations using RNA sequencing. EVs derived from non-trophoblast cells (HEK293) were used as a negative control. The cargo of the EVs were also investigated through mRNA and miRNA sequencing. Trophoblast spheroid derived EVs induced drastic transcriptomic alterations in the endometrial cells while the non-trophoblast cell derived EVs failed to induce such changes demonstrating functional specificity in terms of EV origin. Through gene set enrichment analysis (GSEA), we found that the response in endometrial cells was focused on extracellular matrix remodelling and G protein-coupled receptors' signalling, both of which are of known functional relevance to endometrial receptivity. Approximately 9% of genes downregulated in endometrial cells were high-confidence predicted targets of miRNAs detected exclusively in trophoblast analogue-derived EVs, suggesting that only a small proportion of reduced expression in endometrial cells can be attributed directly to gene silencing by miRNAs carried as cargo in the EVs. Our study reveals that trophoblast derived EVs have the ability to modify the endometrial gene expression, potentially with functional importance for embryo-maternal communication during implantation, although the exact underlying signalling mechanisms remain to be elucidated.