Abstract
Research question
Are M2 macrophages implicated in endometrial invasiveness in adenomyosis?
Design
Seventeen formalin-fixed paraffin-embedded uterine samples and 16 fresh endometrial
biopsies were collected from women with or without adenomyosis. Double immunofluorescence
was performed to determine the predominant macrophage population in adenomyosis between
M1 and M2 phenotypes. The invasion capacity of endometrial cells was assessed by invasion
assays and quantitative polymerase chain reaction for genes involved in cell motility
and epithelial–mesenchymal transition (EMT). Specific mechanisms of invasion were
investigated by immunohistochemistry for E-cadherin, N-cadherin and matrix metalloproteinase
9 (MMP9).
Results
Only M2 macrophages were found to accumulate in adenomyosis, in higher numbers in
both eutopic endometrium (P = 0.0109) and lesions (P = 0.0267) than healthy tissue. Co-culture with M2 macrophages significantly boosted
invasion capacity in endometrial epithelial (P = 0.0002; P = 0.002) and stromal cells (P = 0.0469; P = 0.0047) from both adenomyosis patients and healthy controls. No gene expression
differences indicating EMT were noted, either between co-cultured and control cells,
or between healthy and adenomyotic cells. E- and N-cadherin protein expression did
not differ significantly between endometrium from adenomyosis subjects and healthy
tissue but MMP9 expression was increased in eutopic stroma from adenomyosis patients
(P = 0.0492). In adenomyosis, both E-cadherin (P = 0.0379) and N-cadherin (P = 0.0196) were more extensively expressed in basal glands than functional glands.
Conclusions
M2 macrophages accumulate in adenomyosis and enhance invasion capacity of adenomyotic
and even healthy endometrial cells, implying that macrophage infiltration alone may
be sufficient to promote the disease. This study failed to detect any changes pointing
to EMT, suggesting an alternative mode of invasion. Strong E- and N-cadherin-positive
intercellular junctions in basal (invasive) glands suggest the involvement of collective
cell migration in the invasion process of endometrium.
Keywords
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Biography
Christina Anna Stratopoulou acquired an MSc in Reproductive Biology in 2018 from the University of Thessaly, Greece. She is currently a PhD researcher in the Laboratory of Gynecology at the Catholic University of Louvain, Belgium. Her work focuses essentially on uterine adenomyosis and endometriosis.
Key message
M2 macrophages accumulate in endometrium and ectopic lesions from adenomyosis patients and enhance the invasion capacity of endometrial epithelial and stromal cells by promoting collective cell migration. These findings indicate that M2 macrophages play a key role in disease pathogenesis and could be targeted to develop novel therapeutic options.
Article info
Publication history
Published online: January 09, 2023
Accepted:
January 3,
2023
Received in revised form:
December 12,
2022
Received:
October 11,
2022
Declaration: The authors report no financial or commercial conflicts of interest.Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
