Different macrophages equally induce EMT in endometria of adenomyosis and normal

Abstract

Endometrial cells and microenvironment are two important factors in the pathogenesis of adenomyosis. Our previous study demonstrated that macrophages can induce eutopic epithelial cells of adenomyosis to suffer from epithelial-mesenchymal transition (EMT). The aim of this study is to detect whether macrophages interacting with epithelial cells equally induce the EMT process in normal and eutopic endometria of healthy and adenomyotic patients; and whether macrophages parallelly polarize to M2. We investigated the expression levels of epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), cytokeratin7 (CK7), vimentin, transforming growth factor-β1 (TGFB1), SMAD3 and pSMAD3 using immunohistochemistry and western blot, and then estimated the genetic levels of , and using real-time quantitative polymerase chain reaction (RT-PCR) in macrophages. Eutopic and normal endometrial tissues were obtained from 20 patients with adenomyosis and 11 control patients without adenomyosis, respectively. The immunohistochemical analysis shows distinct EMT in eutopic endometria in secretory phase; the expression levels of TGFB1, SMAD3 and pSMAD3 that indicate signal pathway of EMT were also higher in secretory phase. Macrophages can induce EMT process in primary endometrial epithelial cells derived from normal and eutopic endometria. After co-culturing, THP-1-derived macrophages polarized to M2. Compared with the eutopic endometrium group, further polarization to M2 was observed in the normal endometrium group. These results indicate that adenomyosis may be promoted by the pathologic EMT of epithelial cells, which is induced by macrophages that incapably polarize to M2.

Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review

“…Estrogen is known to induce EMT—the transition of endometrial epithelial cells (associated with a decrease in E-cadherin) to mesenchymal cells, accompanied by an increase in vimentin (Chen et al ., 2010; Ribatti, 2017). This process is linked to angiogenesis, and the same factors that are involved in EMT may drive endothelial cells toward a pro-angiogenic state in adenomyosis (Chen et al ., 2010; Khan et al ., 2015; An et al ., 2017). The presence of EMT was evident by the increased expression of TGF-beta and vimentin and decreased E-cadherin staining in the epithelial cells of the ectopic endometrium in adenomyosis patients (Liu et al .…”

Establishment of Adenomyosis Organoids as a Preclinical Model to Study Infertility

“…In this regard, it has been hypothesized that estrogen is responsible for triggering EMT in adenomyosis [30]. Transforming growth factor (TGF)-β1 and TGF-β2 are growth and differentiation factors involved in EMT induction and regulation [31], which are upregulated in secretory endometrium from patients with adenomyosis [32][33][34], suggesting dysfunctionality during the secretory phase. Further, TGF-β/SMAD (SMAD Family Member 3) signaling is implicated in adenomyosis' pathology [35].…”

Uterine Adenomyosis: From Disease Pathogenesis to a New Medical Approach Using GnRH Antagonists

“…Moreover, single-cell transcriptomic data detected a clear upturn in genes related to cell motility and cancer-like features in adenomyosis [ 19 ]. It has also been hypothesized that estrogen itself drives EMT in adenomyosis, although other studies have proposed inflammation-associated factors as mediators of this process [ 16 , 20 , 21 ].…”

“…A specific interaction with estrogen has been observed in the case of macrophages, which are thought to participate markedly in lesion progression, innervation, and subsequent pain symptoms [ 20 , 40 , 41 ]. According to the invasion theory, hyperestrogenism initially traumatizes the JZ, and inflammatory cells, such as macrophages, accumulate in an attempt to repair the damage, eventually leading to chronic inflammation and more estrogen production [ 15 ].…”