Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity

Suhorutshenko, Marina; Kukushkina, Viktorija; Velthut-Meikas, Agne; Altmäe, Signe; Peters, Maire; Mägi, Reedik; Krjutškov, Kaarel; Koel, Mariann; Codoñer, Francisco M.; Martínez-Blanch, Juan F.; Vilella, Felipe; Simón, Carlos; Salumets, Andres; Laisk, Triin

doi:10.1093/humrep/dey301

Cited by 59 publications

(32 citation statements)

References 63 publications

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“…Cell heterogeneity in the endometrium is not static phenomena—the number and ratio of two dominant cell types in endometrium varies dependent on the menstrual cycle phase [35]. Therefore, the overall changes in gene expression levels in the endometrium are likely to be a consequence of both dynamic alterations in cell composition and in gene expression in each cell type.…”

Section: Discussionmentioning

confidence: 99%

Clues to Non-Invasive Implantation Window Monitoring: Isolation and Characterisation of Endometrial Exosomes

Luddi

Zarovni

Maltinti

et al. 2019

Cells

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Despite the significant advances in the last decades, low implantation rate per transferred embryo still remains a major concern in assisted reproductive techniques, highlighting a need to better characterize endometrial receptivity also by mean of specific biomarkers. Based on physiology and on the intimate contact with endometrium as the tissue of interest, in this study we developed and validated an optimized protocol that uses extracellular vesicles (EVs) recovered from uterine flushings and from a cervical brush, the latter never used until now as an EVs source, as surrogates for endometrial biopsies. This method combines the safety of sampling with the ability to study the expression profile across the uterine cycle. We have compared the yield and composition of EVs recovered from different biofluids samples and fractions thereof, opting for chemical precipitation as the EV isolation procedure, assuring the highest yield without introducing any bias in specific EV recovery. Moreover, collected EVs, in particular exosome-like vesicles, express putative endometrial markers, such as glycodelin A and receptors for estrogen and progesterone, thus confirming their endometrial origin. We also identified uterine flushing EVs, in particular those recovered from its mucous fraction, as the richest source of endometrial transcripts, likely correlated to cellular (epithelial) origin of these vesicles. Finally, our pilot quantitative assessment of three endometrial gene profiles, in samples collected at different time points along the luteal phase, revealed the fluctuations apparently recapitulating gene expression variability prior reported during the menstrual cycle. Unlike tissue biopsy that is subjected to inter- and intra-sample differences, our data suggest that EVs from liquid biopsies (from uterine flushings and a cervical brush) obtained through less-invasive procedures, can be substrate to detect and track the tissue representative expression profiles, better depicting the total endometrium complexity.

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Section: Discussionmentioning

confidence: 99%

Clues to Non-Invasive Implantation Window Monitoring: Isolation and Characterisation of Endometrial Exosomes

Luddi

Zarovni

Maltinti

et al. 2019

Cells

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“…Histological dating was conducted to confirm the endometrial phase. In addition, the receptivity status of all endometrial biopsies was assessed and confirmed by analysing a set of 57 receptivity biomarkers as part of our previous studies [4,24].…”

Section: Methodsmentioning

confidence: 99%

“…For miRNA target gene prediction purposes, mRNA data from our previously published RNA-seq study were retrieved from Gene Expression Omnibus (GSE98386) [4,24]. The mRNA dataset comprised of a subset of the same samples that were used for miRNA analysis in the current study (Figure 1).…”

Section: Methodsmentioning

confidence: 99%

A Two-Cohort RNA-seq Study Reveals Changes in Endometrial and Blood miRNome in Fertile and Infertile Women

Rekker

Altmäe

Suhorutshenko

et al. 2018

Genes

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The endometrium undergoes extensive changes to prepare for embryo implantation and microRNAs (miRNAs) have been described as playing a significant role in the regulation of endometrial receptivity. However, there is no consensus about the miRNAs involved in mid-secretory endometrial functions. We analysed the complete endometrial miRNome from early secretory (pre-receptive) and mid-secretory (receptive) phases from fertile women and from patients with recurrent implantation failure (RIF) to reveal differentially expressed (DE) miRNAs in the mid-secretory endometrium. Furthermore, we investigated whether the overall changes during early to mid-secretory phase transition and with RIF condition could be reflected in blood miRNA profiles. In total, 116 endometrial and 114 matched blood samples collected from two different population cohorts were subjected to small RNA sequencing. Among fertile women, 91 DE miRNAs were identified in the mid-secretory vs. early secretory endometrium, while no differences were found in the corresponding blood samples. The comparison of mid-secretory phase samples between fertile and infertile women revealed 21 DE miRNAs from the endometrium and one from blood samples. Among discovered novel miRNAs, chr2_4401 was validated and showed up-regulation in the mid-secretory endometrium. Besides novel findings, we confirmed the involvement of miR-30 and miR-200 family members in mid-secretory endometrial functions.

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“…Endometrial stromal and epithelial cells have separate, yet complementary and inter-related functions in the endometrial physiology. Significant phase-dependent changes in endometrial tissue cellular composition during the menstrual cycle have been reported [34], and this phenomenon may overshadow the real contribution of each cell type to gene expression variations in the whole-tissue samples. In order to compare the gene expression profile of in vitro cultured organoids and endometrial stromal cells (HESCs) obtained from the same patients, we analyzed a panel of genes previously shown to have a differential expression and likely playing a key regulatory role along with the proceedings through the phases of a menstrual cycle.…”

Section: Differential Gene Expression Profile Between Human Endometrimentioning

confidence: 99%

Organoids of Human Endometrium: A Powerful In Vitro Model for the Endometrium-Embryo Cross-Talk at the Implantation Site

Luddi

Pavone

Semplici

et al. 2020

Cells

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Embryo implantation has been defined as the “black box” of human reproduction. Most of the knowledge on mechanisms underlining this process derives from animal models, but they cannot always be translated to humans. Therefore, the development of an in vitro/ex vivo model recapitulating as closely and precisely as possible the fundamental functional features of the human endometrial tissue is very much desirable. Here, we have validated endometrial organoids as a suitable 3D-model to studying epithelial endometrial interface for embryo implantation. Transmission and scanning electron microscopy analyses showed that organoids preserve the glandular organization and cell ultrastructural characteristics. They also retain the responsiveness to hormonal treatment specific to the corresponding phase of the menstrual cycle, mimicking the in vivo glandular-like aspect and functions. Noteworthy, organoids mirroring the early secretive phase show the development of pinopodes, large cytoplasmic apical protrusions of the epithelial cells, traditionally considered as reliable key features of the implantation window. Moreover, organoids express glycodelin A (GdA), a cycle-dependent marker of the endometrial receptivity, with its quantitative and qualitative features accounting well for the profile detected in the endometrium in vivo. Accordingly, organoids deriving from the eutopic endometrium of women with endometriosis show a GdA glycosylation pattern significantly different from healthy organoids, confirming our prior data on endometrial tissues. The present results strongly support the idea that organoids may closely recapitulate the molecular and functional characteristics of their cells/tissue of origin.

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Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity

Cited by 59 publications

References 63 publications

Clues to Non-Invasive Implantation Window Monitoring: Isolation and Characterisation of Endometrial Exosomes

Clues to Non-Invasive Implantation Window Monitoring: Isolation and Characterisation of Endometrial Exosomes

A Two-Cohort RNA-seq Study Reveals Changes in Endometrial and Blood miRNome in Fertile and Infertile Women

Organoids of Human Endometrium: A Powerful In Vitro Model for the Endometrium-Embryo Cross-Talk at the Implantation Site

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