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Review
. 2023 Dec 4;38(12):2296-2311.
doi: 10.1093/humrep/dead216.

The role of small extracellular vesicle-miRNAs in endometriosis

Affiliations
Review

The role of small extracellular vesicle-miRNAs in endometriosis

Hannah M Nazri et al. Hum Reprod. .

Abstract

Endometriosis is defined by the presence of extrauterine endometrial-like tissue, which can cause pain and infertility in 10% of reproductive-age women. To date, the pathogenesis is poorly understood resulting in significant diagnostic delays and poor therapeutic outcomes in many women. Small extracellular vesicles (sEVs) (<200 nm) are cell-derived vesicles containing molecules that can influence gene expression and behaviour in target cells. One such cargo are microRNAs (miRNAs), which are short, non-coding RNAs mostly 19-25 nucleotides in length that regulate post-transcriptional gene expression. This mini-review focuses on the role of sEV-miRNAs, which are conceivably better biomarkers for endometriosis than free miRNAs, which reflect the true pathophysiological state in the body, as sEV-encapsulated miRNAs are protected from degradation compared to free miRNA and provide direct cell-to-cell communication via sEV surface proteins. sEV-miRNAs have been implicated in the immunomodulation of macrophages, the proliferation, migration and invasion of endometrial cells, and angiogenesis, all hallmarks of endometriosis. The diagnostic potential of sEV-miRNA was investigated in one study that reported the sensitivity and specificity of two sEV-miRNAs (hsa-miR-22-3p and hsa-miR-320a-3p) in distinguishing endometriosis from non-endometriosis cases. Only three studies have explored the therapeutic potential of sEV-miRNAs in vivo in mice-two looked into the role of sEV-hsa-miR-214-3p in decreasing fibrosis, and one investigated sEV-hsa-miR-30c-5p in suppressing the invasive and migratory potential of endometriotic lesions. While early results are encouraging, studies need to further address the potential influence of factors such as the menstrual cycle as well as the location and extent of endometriotic lesions on miRNA expression in sEVs. Given these findings, and extrapolating from other conditions such as cancer, diabetes, and pre-eclampsia, sEV-miRNAs could present an attractive and urgently needed future diagnostic and therapeutic target for millions of women suffering from endometriosis. However, research in this area is hampered by lack of adherence to the International Society for Extracellular Vesicles 2018 guideline in separating and characterising sEVs, as well as the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project protocols.

Keywords: endometriosis; exosomal microRNAs; exosomes; miRNAs; sEV-miRNAs; small extracellular vesicles.

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Conflict of interest statement

None declared by all authors.

Figures

Graphical Abstract
Graphical Abstract
sEV-miRNAs, which can be isolated from all biological fluids, are essential in the pathophysiology of endometriosis, and potentially in the diagnosis and treatment of endometriosis. This figure was created with BioRender.com. sEV-miRNA, small extracellular vesicle-microRNA.
Figure 1.
Figure 1.
The diversity of extracellular vesicles produced by cells in the human body. Compared to exosomes, MVs can be defined as EVs that are released directly from the plasma membrane and are on an average larger than exosomes, although their sizes could range from 30 nm to 1 µm (Jeppesen et al., 2019). The terms ‘ectosomes’ and ‘microparticles’ are synonymously used to describe MVs. Like exosomes, MVs are essential for cellular communication and carry cargo such as mRNA, miRNA, lncRNA, and protein. Apoptotic bodies are released as cells undergo apoptotic cell disassembly, where the plasma membrane blebs and the apoptotic membrane protrudes and fragments. Therefore, different EV subtypes can be categorised according to their biogenesis, size, constituent protein, and isolation methods; however, the different criteria for EV subtypes often overlap, and can even contradict each other. This figure was created with BioRender.com. EV, extracellular vesicle; MV, microvesicle; mRNA, messenger RNA; miRNA, microRNA; lncRNA, long non-coding RNA.
Figure 2.
Figure 2.
Retrograde menstruation is only one part of the endometriosis pathophysiology. (1) Retrograde menstruation brings endometrial cells into the peritoneal cavity. (2) sEVs are produced by all cells (endometrial cells, red blood cells, pMφ, andPMCs) in the peritoneal cavity. (3) sEVs containing miRNAs are taken up by endometrial cells, red blood cells, pMφ, and PMC, causing changes to recipient cells. (4) Uptake of sEVs and internalisation of miRNAs promotes proliferation, migration, and invasion of endometrial cells and of existing ectopic lesions, immunomodulation of macrophages, and potentially EMT changes of PMCs, although none of the studies in this review investigated the impact of sEV-miRNA on PMCs. PF-derived sEVs are likely to originate from a variety of cell types including endometrial cells, red blood cells, immune cells, ectopic lesions, and PMCs. This figure was created with BioRender.com. sEV, small extracellular vesicle; miRNA, microRNA; pMφ, peritoneal macrophage; PMC, peritoneal mesothelial cell; EMT, epithelial-to-mesenchymal transition; PF, peritoneal fluid; sEV-miRNA, small extracellular vesicle-microRNA.
Figure 3.
Figure 3.
Proposed sEV-miRNAs involved in the pathophysiology of endometriosis. sEV-miRNAs involved in the pathophysiology of endometriosis through the proliferation, migration, and invasive potential of endometrial cells, immunomodulation, and angiogenesis (formation of blood vessels) to support explanted endometrial cells (ectopic lesions). Studies also investigated endometriosis-specific miRNAs and the signalling pathways involved. This figure was created with BioRender.com. sEV-miRNA, small extracellular vesicle-microRNA.

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