Human endometrial cell-type-specific RNA sequencing provides new insights into the embryo–endometrium interplay

• Published in: Human reproduction open 2022, Vol.2022 (4), p.1-hoac043
• Main Authors: Koel, Mariann, Krjutškov, Kaarel, Saare, Merli, Samuel, Külli, Lubenets, Dmitri, Katayama, Shintaro, Einarsdottir, Elisabet, Vargas, Eva, Sola-Leyva, Alberto, Lalitkumar, Parameswaran Grace, Gemzell-Danielsson, Kristina, Blesa, David, Simon, Carlos, Lanner, Fredrik, Kere, Juha, Salumets, Andres, Altmäe, Signe
• Format: Article
• Language: English
• Subjects: Blastocyst; embryo implantation; Embryonic development; endometrial epithelium; endometrial receptivity; endometrial stroma; Endometrium; Epithelium; Genetic aspects; Human embryo; interactome; Medicin och hälsovetenskap; Obstetrical research; Physiological aspects; RNA sequencing; Transplantation
• ISSN: 2399-3529; 2399-3529
• DOI: 10.1093/hropen/hoac043

STUDY QUESTION Which genes regulate receptivity in the epithelial and stromal cellular compartments of the human endometrium, and which molecules are interacting in the implantation process between the blastocyst and the endometrial cells? SUMMARY ANSWER A set of receptivity-specific genes in the endometrial epithelial and stromal cells was identified, and the role of galectins (LGALS1 and LGALS3), integrin β1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in embryo–endometrium dialogue among many other protein–protein interactions were highlighted. WHAT IS KNOWN ALREADY The molecular dialogue taking place between the human embryo and the endometrium is poorly understood due to ethical and technical reasons, leaving human embryo implantation mostly uncharted. STUDY DESIGN, SIZE, DURATION Paired pre-receptive and receptive phase endometrial tissue samples from 16 healthy women were used for RNA sequencing. Trophectoderm RNA sequences were from blastocysts. PARTICIPANTS/MATERIALS, SETTING, METHODS Cell-type-specific RNA-seq analysis of freshly isolated endometrial epithelial and stromal cells using fluorescence-activated cell sorting (FACS) from 16 paired pre-receptive and receptive tissue samples was performed. Endometrial transcriptome data were further combined in silico with trophectodermal gene expression data from 466 single cells originating from 17 blastocysts to characterize the first steps of embryo implantation. We constructed a protein–protein interaction network between endometrial epithelial and embryonal trophectodermal cells, and between endometrial stromal and trophectodermal cells, thereby focusing on the very first phases of embryo implantation, and highlighting the molecules likely to be involved in the embryo apposition, attachment and invasion. MAIN RESULTS AND THE ROLE OF CHANCE In total, 499 epithelial and 581 stromal genes were up-regulated in the receptive phase endometria when compared to pre-receptive samples. The constructed protein–protein interactions identified a complex network of 558 prioritized protein–protein interactions between trophectodermal, epithelial and stromal cells, which were grouped into clusters based on the function of the involved molecules. The role of galectins (LGALS1 and LGALS3), integrin β1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in the embryo implantation process were highlighted. LARGE SCALE DATA RNA-seq data are available at www.ncbi.nlm.nih.gov/geo under accession number GSE97929. LIMITATIONS,