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During reproductive life, the human endometrium undergoes around 480 cycles of growth, breakdown and regeneration should pregnancy not be achieved. This outstanding regenerative capacity is the basis for women's cycling and its dysfunction may be involved in the etiology of pathological disorders. Therefore, the human endometrial tissue must rely on a remarkable endometrial somatic stem cells (SSC) population. Here we explore the hypothesis that human endometrial side population (SP) cells correspond to somatic stem cells. We isolated, identified and characterized the SP corresponding to the stromal and epithelial compartments using endometrial SP genes signature, immunophenotyping and characteristic telomerase pattern. We analyzed the clonogenic activity of SP cells under hypoxic conditions and the differentiation capacity in vitro to adipogenic and osteogenic lineages. Finally, we demonstrated the functional capability of endometrial SP to develop human endometrium after subcutaneous injection in NOD-SCID mice. Briefly, SP cells of human endometrium from epithelial and stromal compartments display genotypic, phenotypic and functional features of SSC.

Our results reveal that elevated progesterone levels on the day of rCG administration can induce significant alterations in the gene expression profile of the endometrium.

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MicroRNAs (miRNAs) act as important epigenetic posttranscriptional regulators of gene expression. We aimed to gain more understanding of the complex gene expression regulation of endometrial receptivity by analyzing miRNA signatures of fertile human endometria. We set up to analyze miRNA signatures of receptive (LH þ 7, n ¼ 4) versus prereceptive (LH þ 2, n ¼ 5) endometrium from healthy fertile women. We found hsa-miR-30b and hsa-miR-30d to be significantly upregulated, and hsa-miR-494 and hsa-miR-923 to be downregulated in receptive endometrium. Three algorithms (miRanda, PicTar, and TargetScan) were used for target gene prediction. Functional analyses of the targets using Ingenuity Pathways Analysis and The Database for Annotation, Visualization and Integrated Discovery indicated roles in transcription, cell proliferation and apoptosis, and significant involvement in several relevant pathways, such as axon guidance, Wnt/b-catenin, ERK/MAPK, transforming growth factor b (TGF-b), p53 and leukocyte extravasation. Comparison of predicted miRNA target genes and our previous messenger RNA microarray data resulted in a list of 12 genes, including CAST, CFTR, FGFR2, and LIF that could serve as a panel of genes important for endometrial receptivity. In conclusion, we suggest that a subset of miRNAs and their target genes may play important roles in endometrial receptivity.

Successful embryo implantation depends on the quality of the embryo, as well as on the receptivity of the endometrium. The aim of this study was to investigate the endometrial gene expression profile in women with unexplained infertility in comparison with fertile controls at the time of embryo implantation in order to find potential predictive markers of uterine receptivity and to identify the molecular mechanisms of infertility. High-density oligonucleotide gene arrays, comprising 44 000 gene targets, were used to define the endometrial gene expression profile in infertile (n = 4) and fertile (n = 5) women during the mid-secretory phase (day LH + 7). Microarray results were validated using real-time PCR. Analyses of expression data were carried out using non-parametric methods. Hierarchical clustering and principal component analysis showed a clear distinction in endometrial gene expression between infertile and fertile women. In total we identified 145 significantly (>3-fold change) up-regulated and 115 down-regulated genes in infertile women versus controls. Via Database for Annotation, Visualization and Integrated Discovery functional analysis we detected a substantial number of dysregulated genes in the endometria of infertile women, involved in cellular localization (21.1%) and transport (18.8%) and transporter activity (13.1%) and with major localization in extracellular regions (19.2%). Ingenuity Pathways Analysis of the gene list showed dysregulation of gene pathways involved in leukocyte extravasation signalling, lipid metabolism and detoxification in the endometria of infertile women. In conclusion, endometrial gene expression in women with unexplained infertility at the time of embryo implantation is markedly different from that in fertile women. These results provide new information on genes and pathways that may have functional significance as regards to endometrial receptivity and subsequent embryo implantation.

We demonstrated that the murine endometrium possesses LRCs with the features of a putative PSC population localized at the lower region of the stroma.