Study question Is the percentage of endometrial stem cells linked to serum progesterone, serum estradiol, and their receptors expression in human endometrium during the mid-luteal phase? Summary answer We found an association between CD117+ endometrial stem cells and serum progesterone, estradiol, as well as with the expression of their receptors in the endometrium. What is known already Various types of stem cells including NOTCH1+ and CD117+ stromal cells have been found in the endometrium. Their quantities have been hypothesised to fluctuate with the menstrual cycle and to have a link with endometrial receptivity. It has been well established that progesterone and estradiol play a crucial role in the preparation of the endometrium for implantation and the expression of their receptors also varies with the menstrual cycle. Nonetheless, the relationship between stem cells and other established markers of endometrial receptivity, such as the sex hormones signaling system, constitutes a novel field of research. Study design, size, duration The present observational study included 87 women aged 26-56 (mean 39.5 years old) undergoing in-vitro fertilisation and for whom a peripheral blood sample and an endometrial biopsy were obtained during the mid-luteal phase (LH + 7) of a natural cycle. Immunohistochemical (IHC) markers for NOTCH1 (E-AB-12815, Elabscience), CD117 (CD117/c-Kit/SCF-Receptor RB-9038-RQ, Epredia), progesterone (PR) and estrogen receptors (ER) (1-PR026-07, 1-ES006-07, Quartett) were used to stain endometrial tissue. The investigation was carried out between March 2020 and January 2022. Participants/materials, setting, methods Serum progesterone and estradiol were measured via electrochemiluminescence using Cobas e411 analyser (Roche Diagnostics, Germany) on the day of obtaining the endometrial biopsy. Stem cells (count and percentage) and the expression of hormone receptors (6-point scale) were determined using ImageJ. Stem cells percentage was compared between groups with high and low progesterone (analogously for estradiol) using Wilcoxon signed-rank test. To assess the link between stem cell percentages and receptor expression, Spearman correlation was used. Main results and the role of chance The mean percentage of positively stained NOTCH1 endometrial stromal stem cells was 0.13 ± 0.29% and CD117+ cells was 0.034 ± 0.039%. The hormone serum levels ranged from 0.2 to 60 ng/mL (median of 14.9 ng/mL) for progesterone and from 12 to 1985 pg/mL (median of 135.6 pg/mL) for estradiol. While the quantities of the two stem cell types demonstrated a positive correlation with each other (R = 0.379, p < 0.001), the percentage of NOTCH1+ stem cells showed no difference between the studied serum hormone levels (p > 0.05), nor revealed a relationship with the expression of their receptors (p > 0.05). In contrast, the amount of CD117+ cells differed significantly between patients with high and low serum progesterone (cutoff 14.9 ng/mL, p = 0.001) and estradiol levels (cutoff 135.6 pg/mL, p = 0.019). Furthermore, the quantity of stem cells positive for CD117 correlated positively with the two hormone receptor levels in the endometrium – PR (R = 0.277, p = 0.019) and ER (R = 0.318, p = 0.007). Limitations, reasons for caution A limitation of the study was the sample size. These findings should be confirmed using a larger population. In addition, confounding variables such as the immunological profile of the tissue should also be taken into account. Wider implications of the findings This study shows that certain endometrial stem cell types (CD117+) but not others (NOTCH1+) are associated with sex hormone signaling during the mid-luteal phase. This relationship highlights the role these cells play in preparing the endometrium for embryo implantation and their quantity might be an indirect indicator of endometrial receptivity. Trial registration number not applicable
Study question Is there a relationship between the percentage of stem cells in human endometrial stroma during the mid-luteal phase of the menstrual cycle and implantation success? Summary answer Women with successful implantation have significantly higher percentage of endometrial stromal CD117-positive stem cells during the mid-luteal phase of the menstrual cycle. What is known already Human endometrium as a highly regenerative dynamic tissue has a population of certain types of adult stem cells localized in the stroma and epithelium. These cells, including mesenchymal and hematopoietic stromal stem cells, participate in the immense cellular turnover in the human endometrium before and during the implantation process. General adult stem cell markers such as CD117 and NOTCH1 have been identified in human endometrium. However, there is a scarce data about the quantity of these endometrial stromal stem cells and their influence on the process of implantation. Study design, size, duration This is a cohort study of 109 women who had an endometrial biopsy during the mid-lutheal phase (LH + 7) in a natural cycle and positive or negative hCG test after in-vitro fertilization (IVF) with euploid embryos within 6 months of biopsy. We used immunohistochemical biomarkers NOTCH1 (E-AB-12815, Elabscience), CD117 (CD117/c-Kit/SCF-Receptor) (RB-9038-RQ, Epredia), to identify stem cells in endometrial stroma. The study was conducted between March 2020 and January 2022. Participants/materials, setting, methods The percentages of NOTCH1-positive and CD117-positive stem cells in the stroma were calculated after enumeration by two independent investigators in multiple endometrial sections. After embryo transfer women were divided into the following groups: unsuccessful embryo implantation (negative hCG test) ( n = 45) and successful implantation (positive hCG test) ( n = 64). The percentage of NOTCH1-positive and CD117-positive cells in the endometrial stroma were compared between these groups through Wilcoxon signed-rank test. Main results and the role of chance The percentage of CD117-positive stem cells in the endometrial stroma ranged between 0% and 0.21%, with a median of 0.02%. The percentage of NOTCH1-positive stem cells in the endometrial stroma ranged between 0.003% and 2.11%, with a median of 0.06%. There was no significant difference in female age (years), BMI (kg/m2) and blastocyst quality between the studied patient groups (P < 0.05). The quantity of NOTCH1-positive cells also did not differ significantly between the two groups (P = 0.18). However, the mean percentage of CD117-positive stromal cells was significantly higher in women with successful implantation compared to patients with unsuccessful implantation (0.04% vs. 0.02%, respectively, P = 0.004). The optimal successful implantation cut-off value for the percentage of CD117-positive stromal cells, was 0.018% (AUC 0.67, 95% CI 0.56-0.77). Therefore, a percentage of 0.018% of CD117-positive stem cells in the endometrial stroma was associated with 63.1% sensitivity and 61.4% specificity for predicting successful implantation after IVF. Limitations, reasons for caution The study cohort was limited in sample size. Not all confounding factors such as potential immunological and genetic reasons for unsuccessful implantation have been taken into account. In addition, the endometrial biopsy could also have an effect on endometrial receptivity and pregnancy outcome. Wider implications of the findings The results of this study revealed that the quantity of certain types of stem cells is associated with successful embryo implantation. These findings emphasize the essential impact of stem cells in human endometrium on the process of implantation. Trial registration number not applicable
Study question Are endometrial stem cells associated with endometrial immune cell populations during the window of implantation? Summary answer Endometrial stem cells are associated with the presence of macrophages and B-cells, but do not correlate to T-cells and natural killer (NK) cells. What is known already The endometrial stem cells are essential for the periodic uterine regeneration. Besides their role in tissue remodeling it has been recently shown that they exert immunomodulatory and anti-inflammatory effect on the components of the immune system. A well known fact is that the immune cell composition of the endometrium during the window of implantation is pivotal for the successful embryo implantation. There are only a few publications that study the association of the endometrial stem cells with the immune cells with regard to the window of implantation. Study design, size, duration Single center prospective study analyzing the cell composition of endometrial samples from women undergoing IVF. A total of 109 patients without endometrial pathologies were recruited for endometrial biopsy between March 2020 and January 2022. Endometrial samples were obtained on day 7 after LH peak in the presumed window of implantation and processed to formalin-fixed, paraffin-embedded slices for immunohistochemical analysis. This study received the approval of the hospital’s medical ethics committee. Participants/materials, setting, methods Tissue sections were immunohistochemically stained for CD117 and NOTCH1 as stem cell markers as well as for immune cells with CD3 (T-cells), CD8 (T-killers), CD4 (T-helpers), CD56 (NK cells), CD68 (Macrophages), CD14 (Macrophages) and CD79α (B-cells) antibodies. The percentage of positively stained stromal cells was evaluated by Image-J software in the same tissue area for each sample. Statistical analysis: Spearman correlation, p < 0.05 was considered significant. Main results and the role of chance Immunohistochemical analysis showed that NOTCH1 and CD117 positive stem cells are present in all samples with mean 0.133±0.029% and 0.034±0.004%, respectively, and they were significantly correlated (R = 0.397, p < 0.001). The presence of CD3+ T-cells, CD4+ T-helpers, CD8+ T-killers, CD56+ NK cells, CD79α+ B cells, CD68+ macrophages, CD14+ macrophages was also confirmed with mean 1.133±0.259%, 0.374±0.058%, 0.074±0.013%, 0.883±0.184%, 0.188±0.060%, 1.018±0.202% and 1.309±0.257%, respectively. Spearman analysis revealed significant positive correlation between NOTCH1 positive stem cells and CD79α+ B-cells (R = 0.211, p = 0.029), CD14+ macrophages (R = 0.231, p = 0.017), but no relation to the other studied immune cell types was observed (p > 0.05). Significant positive correlation between CD117 positive stem cells and CD14+ macrophages (R = 0.262, p = 0.007), CD68+ macrophages (R = 0.216, p = 0.025) and no relation to the other studied immune cell types was observed (p > 0.05). When the immune cells ratios were evaluated and analysed for correlation with stem cells, it turned out that only CD117 positive stem cells are significantly correlated to CD8+ T-killers/CD68+ macrophages ratio (R=-0.274, p = 0.007). Limitations, reasons for caution In this study only immunohistochemical analysis was used. In future studies flowcytometrical quantification of the studied cells will be used. Also more immune cell subtypes should be included in the analysis to further characterise the stem cells association to the immune cell populations. Wider implications of the findings During the window of implantation the endometrial stem cells are associated to the macrophages distribution. In contrast to NOTCH1+, CD117+ stem cells relate to the endometrial B-cells. These findings confirm the role of the endometrial stem cells in the fine tuning of the immune behavior during the window of implantation. Trial registration number Not Applicable
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