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Time-series single-cell transcriptomic profiling of luteal-phase endometrium uncovers dynamic characteristics and its dysregulation in recurrent implantation failures

ABSTRACT: Understanding human endometrial dynamics remains a challenge, limiting early diagnosis and treatment of reproductive disorders. Here, we decoded the normal endometrial dynamics across the window of implantation (WOI) and its deficiency in endometrium from women with recurrent implantation failure (RIF) by analyzing data from over 220,000 cells, together with developing a computational model StemVAE that is capable of both temporal prediction and pattern discovery. Our time-series atlas highlighted a two-stage stromal decidualization process whereas a gradual epithelial transitional process across the WOI allowing the identification of a time-varying gene set regulating epithelial receptivity. The epithelial receptivity genes were able to stratify the RIF endometrium into two classes of receptivity-deficiency involving early and late implantation. Further investigation uncovered epithelial cell dysfunction under hyperinflammatory microenvironment in RIF endometrium. The holistic characterization of physiological and pathophysiological WOI, and a computational tool trained on this temporal atlas provide a platform for future therapeutic developments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250130 | GEO | 2024/11/18

REPOSITORIES: GEO

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Project description:Study question: Does a comprehensive study involving two different population cohorts and small RNA sequencing from endometrium and blood reveal new endometrial receptivity-related microRNAs (miRNAs) in healthy conditions and in women with recurrent implantation failure (RIF)? Summary answer: Several annotated miRNAs, not previously associated with endometrial receptivity, as well as one novel miRNA were found as differentially expressed between early secretory vs. mid-secretory phase samples in addition to miRNAs dysregulated in RIF patients. What is known already: The involvement of miRNAs in mid-secretory endometrial functions has been shown and aberrant expression of miRNAs in RIF has been identified in a few previous studies, but not from whole blood samples. However, as the analysis settings and platforms have been different and a small number of samples has been analysed, there is no consensus about the miRNAs involved in endometrial receptivity and dysfunction. Participants/materials, setting, methods: A total of 116 endometrial and 114 blood samples were subjected to Illumina small RNA sequencing. Identification of annotated and novel miRNAs from sequencing reads was performed by miRDeep2 algorithm. miRNAs that had significantly altered levels between the study groups in both EST and ESP datasets were considered as differentially expressed. Ingenuity Pathway Analysis was applied for identifying miRNA target genes and respective canonical pathways from the matched mRNA analysis from the same samples. Custom TaqMan Small RNA assay was used for the validation of novel miRNA (chr2_4401) levels from paired early secretory and mid-secretory endometrial samples. Main results and the role of chance: Among fertile women, 91 differentially expressed miRNAs were identified in mid-secretory vs. early secretory endometrium, while no differentially expressed miRNAs were found in the corresponding blood samples. The comparison of mid-secretory phase samples between fertile women and RIF patients revealed 21 differentially expressed miRNAs from endometrium and one from blood samples. miRNA target gene prediction analysis using our mRNA sequencing data from the matched samples detected several canonical pathways to be involved in mid-secretory endometrial functions, including JAK/STAT signalling, leptin signalling and growth hormone signalling. Moreover, JAK/STAT signalling pathway was also revealed in miRNA target analysis of mid-secretory endometrium from RIF patients when compared to fertile women. Further, our study results highlight the involvement of miR-30 and miR-200 families in endometrial receptivity, and miR-424-5p in the development of endometrial dysfunction. We identified several novel miRNAs, of which miRNA chr2_4401, being 37-fold up-regulated in mid-secretory phase, has a potential role in the mid-secretory endometrial functions. From blood samples we identified miR-30a-5p as a possible marker of infertility related to RIF.

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Time-series single-cell transcriptomic profiling of luteal-phase endometrium uncovers dynamic characteristics and its dysregulation in recurrent implantation failures

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