子宫腺肌病子宫内膜类器官分泌的细胞外囊泡含有参与胚胎着床和妊娠的微小RNA。

Extracellular vesicles secreted by adenomyosis endometrial organoids contain miRNAs involved in embryo implantation and pregnancy.

作者信息

Juárez-Barber Elena, Segura-Benítez Marina, Carbajo-García María Cristina, Bas-Rivas Alba, Faus Amparo, Vidal Carmen, Giles Juan, Labarta Elena, Pellicer Antonio, Cervelló Irene, Ferrero Hortensia

机构信息

Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain.

Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, 46010 Valencia, Spain.

出版信息

Reprod Biomed Online. 2023 Mar;46(3):470-481. doi: 10.1016/j.rbmo.2022.12.008. Epub 2022 Dec 18.

DOI:10.1016/j.rbmo.2022.12.008

PMID:36697316

Abstract

RESEARCH QUESTION

Do extracellular vesicles secreted by the endometrium of women with adenomyosis contain miRNAs involved in adenomyosis-related infertility?

DESIGN

A descriptive study using organoids from eutopic endometrium of women with adenomyosis (n = 4) generated and differentiated to secretory and gestational phases, in which miRNA cargo from extracellular vesicles secreted by these differentiated organoids in each phase was analysed by next-generation sequencing. miRNAs in secretory-extracellular vesicles and gestational-extracellular vesicles were selected based on the counts per million. miRNAs target genes in each phase were obtained from miRNet and gene ontology was used for enrichment analysis.

RESULTS

miRNA sequencing identified 80 miRNAs in secretory-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-24-3p, hsa-miR-26a-5p, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-200c-3p and hsa-miR-423a-5p, related to adenomyosis pathogenesis and implantation failure. Further, 60 miRNAs were identified in gestational-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-26a-5p, hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-222-3p and hsa-miR-423a-5p were associated with preeclampsia and miscarriage. Among the target genes of these miRNAs, PTEN, MDM4, PLAGL2 and CELF1, whose downregulation (P = 0.0003, P < 0.0001, P = 0.0002 and P = 0.0003, respectively) contributes to adenomyosis pathogenesis, and impaired early embryo development, leading to implantation failure and miscarriage, are highlihghted. Further, functional enrichment analyses of the target genes revealed their involvement in cell differentiation, proliferation, apoptosis, cell cycle regulation and response to extracellular stimuli.

CONCLUSIONS

Eutopic endometrium in secretory and gestational phase from women with adenomyosis releases extracellular vesicles containing miRNAs involved in adenomyosis progression, impaired embryo implantation and pregnancy complications.

摘要

研究问题

子宫腺肌病患者子宫内膜分泌的细胞外囊泡是否含有与子宫腺肌病相关不孕症有关的微小RNA（miRNA）？

设计

一项描述性研究，使用子宫腺肌病患者（n = 4）在位内膜的类器官，将其生成并分化至分泌期和妊娠期，通过下一代测序分析这些分化类器官在每个阶段分泌的细胞外囊泡中的miRNA负载。基于每百万计数选择分泌期细胞外囊泡和妊娠期细胞外囊泡中的miRNA。从miRNet获得每个阶段miRNA的靶基因，并使用基因本体进行富集分析。

结果

miRNA测序在分泌期细胞外囊泡中鉴定出80种miRNA，包括hsa-miR-21-5p、hsa-miR-24-3p、hsa-miR-26a-5p、hsa-miR-92a-3p、hsa-miR-92b-3p、hsa-miR-200c-3p和hsa-miR-423a-5p，与子宫腺肌病发病机制和植入失败有关。此外，在妊娠期细胞外囊泡中鉴定出60种miRNA，包括hsa-miR-21-5p、hsa-miR-26a-5p、hsa-miR-30a-5p、hsa-miR-30c-5p、hsa-miR-222-3p和hsa-miR-423a-5p，与子痫前期和流产有关。在这些miRNA的靶基因中，PTEN、MDM4、PLAGL2和CELF1的下调（分别为P = 0.0003、P < 0.0001、P = 0.0002和P = 0.0003）导致子宫腺肌病发病机制以及早期胚胎发育受损，导致植入失败和流产，这些被重点强调。此外，靶基因的功能富集分析揭示它们参与细胞分化、增殖、凋亡、细胞周期调控以及对细胞外刺激的反应。