Estrogen promotes the survival of human secretory phase endometrial stromal cells via CXCL12/CXCR4 up-regulation-mediated autophagy inhibition

Jie Mei, Xiao-Yong Zhu, Xiao‐Yong Zhu, Li-Pin Jin, Zhongliang Duan, Zhong-Liang Duan, Da-Jin Li, Da‐Jin Li, Ming‐Qing Li, Ming-Qing Li
Human Reproduction · 2015 · vol. 30(7) , pp. 1677–1689 · doi:10.1093/humrep/dev100 · PMID:25976655 · W1897969243
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Estrogen promotes secretory phase endometrial stromal cell survival by up-regulating CXCL12/CXCR4 to inhibit autophagy, leading to reduced apoptosis.

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Abstract

STUDY QUESTION: What mechanism is involved in regulating the autophagy of endometrial stromal cells (ESCs), and does it participate in the pathogenesis of endometriosis? SUMMARY ANSWER: CXCL12 down-regulates secretory phase ESC autophagy. WHAT IS KNOWN ALREADY: mTOR (mammalian target of rapamycin), the major negative regulator of autophagy, is abnormally increased in endometriotic lesions and is involved in the direct regulation of endometrial stromal cell (ESC) apoptosis. STUDY DESIGN, SIZE, DURATION: Autophagy was measured by transmission electron microscopy and immunofluorescence, and in vitro analysis was used to measure estrogen/CXCL12/CXCR4 signaling-mediated ESC autophagy. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 31 controls and 31 women with histologically confirmed endometriosis were included. We measured the autophagy level of normal and endometriosis-derived endometrium, and its relationship to the stage of endometriosis, as well as the potential molecular and signaling pathways that mediate the aberrant autophagy in endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with control secretory phase ESCs, a significant reduction of the autophagy grade (as observed in TEM), punctuate LC3B staining (as observed in immunofluorescence assays), and autophagy-associated protein levels were exhibited in secretory phase eutopic ESCs (P < 0.05) and ectopic ESCs (P < 0.05) from women with endometriosis. In addition, the autophagy level was strongly negatively correlated with the CXCL12 concentration in ESCs (R(2) = -0.9694). However, there was no significant difference in autophagy grade or CXCL12 concentration between stage I-II and stage III-IV endometriosis-derived ectopic ESCs (P > 0.05). Based on a human autophagy PCR array, CXCL12 and CXCR4, which is the CXCL12 receptor, in ESCs were predicted to be molecules that mediate the abnormally lower autophagy in endometriosis. Accordingly, after estradiol (E2) treatment a marked increase in CXCL12 secretion (1.71-fold, P < 0.01) and CXCR4 expression (5.07-fold, P < 0.01) in secretory phase ESCs was observed together with decreases in autophagy grade (TEM), punctuate LC3B immunofluorescent staining and autophagy-associated protein levels (P < 0.05). These changes could be reversed by progesterone (P4) (P < 0.05). The suppression of autophagy induced by E2 and recombinant human CXCL12 protein could be abrogated by an anti-CXCR4 neutralizing antibody and by a NF-κB inhibitor (P < 0.05), respectively. In addition, estrogen-stimulated CXCL12 secretion led to a low population of S phase cells (P < 0.05), as well as a low level of apoptosis (P < 0.05) in secretory phase ESCs. LIMITATIONS, REASONS FOR CAUTION: Further studies are needed to examine the mechanism of autophagy on ESC apoptosis. WIDER IMPLICATIONS OF THE FINDINGS: Measures to increase in endometrial autophagy might be a valid, novel approach to reduce local E2-dependent growth of endometriotic tissue. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Natural Science Foundation of China (NSFC) (81471513, 81471548 and 81270677), the Training Program for Young Talents of Shanghai Health System XYQ2013104, the Program for Zhuoxue of Fudan University, and the Program for Creative Talents Education of Key Disciplines of Fudan University. None of the authors has any conflict of interest to declare.

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Condition tags

endometriosis

MeSH descriptors

Autophagy Chemokine CXCL12 Endometriosis Endometrium Estrogens Receptors, CXCR4 Signal Transduction Stromal Cells Adult Autophagy Chemokine CXCL12 Endometriosis Endometriosis Endometrium Endometrium Estrogens Estrogens Female Humans Receptors, CXCR4

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