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This doctoral thesis investigated the role of small extracellular vesicles (sEV) in the peritoneal microenvironment of endometriosis, focusing on bidirectional communication between macrophages and lesion-derived epithelial organoids. Using flow cytometry and nanoparticle tracking analysis, the study characterized sEV surface markers from peritoneal fluid, macrophages, and organoids, revealing distinct profiles based on cellular origin and hormonal treatment status. Functional assays demonstrated that sEV from both peritoneal fluid and lesions impaired macrophage phagocytic activity through the CD47/SIRP-alpha pathway, although no significant differences were found between endometriosis patients and controls regarding biomarker potential. This paper is centrally about endometriosis — specifically examining the mechanisms by which extracellular vesicles modulate immune cell function within the disease's peritoneal environment.
Abstract
Endometriosis is characterised by the growth of endometrium like tissue outside the uterus (lesions). Small extracellular vesicles (sEV) in the peritoneal microenvironment of endometriosis modulate intracellular communication and disease progression. This study aimed to characterize the cellular origins of sEV, examine their potential as biomarkers, and investigate their functional role in disease progression by affecting macrophage phagocytic activity.Using MACSPlex EV flow cytometry and Nanoparticle Tracking Analysis (NTA), the size, concentration, and surface epitopes of sEV from peritoneal fluid (PF), in vitro cultured peritoneal macrophages (pMΦ), and endometrial/lesion derived epithelial organoids (EEO) were characterised.Flow cytometry revealed distinct sEV profiles from different cellular origins: CD14 and HLA-DR on pMΦ -sEV, and EpCAM and CD133/1 on EEO-sEV. EEO-sEV from lesions expressed higher levels of CD44 and CD29 compared to EEO-sEV from eutopic endometrium. High expression of HLA-DR, EpCAM, and CD133/1 in PF-sEV indicated a predominance of epithelial derived and pMΦ -sEV. Hormonal treatment (HT) was associated with lower EpCAM and higher CD24 expression on PF-sEV. However, no differences were found between endometriosis and control patients. NTA showed lower PF-sEV concentration in HT compared to non-HT. EEO polarity also affected EV size and concentration. Functional analysis revealed impairment of macrophage phagocytic activity (assays using pH-sensitive pHrodo E.coli bioparticles) by PF-sEV and lesion EEO-sEV, mediated through the CD47/SIRP-alpha.This study revealed the complexity of sEV profiles predominantly from antigen-presenting cells and endometrial epithelial cells. While sEV profiles were distinct from different sources and reflected environmental changes like HT, their use as biomarkers requires further investigation. The functional roles of EV in disease progression potentially extend beyond impairing macrophage phagocytosis as demonstrated in this study, as these sEV expressed various functionally important markers.
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Thesis
Extracellular vesicle-mediated bidirectional communication between macrophages and lesions in the peritoneal microenvironment of endometriosis
- Abstract:
-
Endometriosis is characterised by the growth of endometrium like tissue outside the uterus (lesions). Small extracellular vesicles (sEV) in the peritoneal microenvironment of endometriosis modulate intracellular communication and disease progression. This study aimed to characterize the cellular origins of sEV, examine their potential as biomarkers, and investigate their functional role in disease progression by affecting macrophage phagocytic activity.
Using MACSPlex EV flow cytometry and Nanoparticle Tracking Analysis (NTA), the size, concentration, and surface epitopes of sEV from peritoneal fluid (PF), in vitro cultured peritoneal macrophages (pMΦ), and endometrial/lesion derived epithelial organoids (EEO) were characterised.
Flow cytometry revealed distinct sEV profiles from different cellular origins: CD14 and HLA-DR on pMΦ -sEV, and EpCAM and CD133/1 on EEO-sEV. EEO-sEV from lesions expressed higher levels of CD44 and CD29 compared to EEO-sEV from eutopic endometrium. High expression of HLA-DR, EpCAM, and CD133/1 in PF-sEV indicated a predominance of epithelial derived and pMΦ -sEV. Hormonal treatment (HT) was associated with lower EpCAM and higher CD24 expression on PF-sEV. However, no differences were found between endometriosis and control patients. NTA showed lower PF-sEV concentration in HT compared to non-HT. EEO polarity also affected EV size and concentration. Functional analysis revealed impairment of macrophage phagocytic activity (assays using pH-sensitive pHrodo E.coli bioparticles) by PF-sEV and lesion EEO-sEV, mediated through the CD47/SIRP-alpha.
This study revealed the complexity of sEV profiles predominantly from antigen-presenting cells and endometrial epithelial cells. While sEV profiles were distinct from different sources and reflected environmental changes like HT, their use as biomarkers requires further investigation. The functional roles of EV in disease progression potentially extend beyond impairing macrophage phagocytosis as demonstrated in this study, as these sEV expressed various functionally important markers.
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Authors
Contributors
+ Becker, C
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Women's & Reproductive Health
- Role:
- Supervisor
+ Southcombe, J
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Women's & Reproductive Health
- Role:
- Supervisor
- ORCID:
- 0000-0003-0699-650X
+ Dragovic, R
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Women's & Reproductive Health
- Role:
- Supervisor
- ORCID:
- 0000-0002-4634-5165
+ Erin, G
- Institution:
- University of Warwick
- Role:
- Supervisor
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
-
English
- Keywords:
- Subjects:
- Deposit date:
-
2026-05-11
- ARK identifier:
Terms of use
- Copyright holder:
- Yifan Wang
- Copyright date:
- 2024
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