(3)ヒト着床における子宮内膜腺上皮の複合的機能の分子制御(シンポジウム2「子宮内膜の機能調節とその病態」,第62回日本産科婦人科学会・学術講演会)

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  • 内田,浩
    慶應義塾大学医学部産婦人科学教室

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  • Molecular Mechanism of Multiple and Orchestrated Functions in Endometrial Epithelial Cells during Human Implantation

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Recent developed technology in assisted reproductive technologies (ART) has resulted in higher fertilization rates for infertile couples. However, failure of the embryo implantation to endometrial epithelial cells (EECs) blocks successful pregnancy. For EEC dynamics, human implantation can be divided into the multiple steps of processes, which are apposition and adhesion to the embryo, destruction to make space for embryo penetration and reconstruction to cover undefended penetrating and invading embryo. Human implantation can be redefined a multi-step event requiring the orchestrated regulation of EECs, involving cell proliferation, differentiation, motility, and adhesion. Reversible histone acetylation regulates gene transcription and histone deacetylase inhibitors (HDACI) induce specific genes. Recently, it is reported that HDACIs can induce differentiation in various typed of cells including human endometrial stromal cells (ESCs). Because of the temporospacial expression pattern, which is highly expressed during implantation window in EEC, a progesterone-induced EEC protein, Glycodelin is one of the differentiation markers of EEC. To elucidate the EEC dynamics, we performed a variety of cell assays using human endometrial epithelial cell line, Ishikawa cells, and human trophoblastic cell line, JAR, as an EEC and an embryo model, respectively. By treatment of Ishikawa cells with ovarian steroid hormones (estradiol plus progesterone; EP) or one of HDACI, suberoylanilide hydroxamic acid (SAHA), resulted in the following observations. Glycodelin promoter activity was accelerated in promoter assay. Glycodelin expression was upregulated at both mRNA and protein level. Through upregulation of Glycodelin expression, flattened and wide-spreaded morphological change was observed and Glycogen synthesis, which indicates EEC functional differentiation, was upregulated. These results indicate that ovarian steroid hormones can induce cell differ entiation without signal from embryo. It is known that alteration of EEC polarity is required for human implantation. In motile status of epithelial cells, such as translocation of differentiated cells to appropriate area in early development, or invasion of malignant cells, epithelial cells morphologically and characteristically exchange to mesenchymal-like cells. This phenomenon is called 'Epithelial mesenchymal transition (EMT)'. During EMT, cell polarity is exchanged. By treatment of EP or SAHA, the expression of vinculin, one of mesenchymal cell markers, was upregulated. Both downregulation of E-cadherin and upregulation of N-cadherin, which is named 'cadherin switch' and characteristic to EMT, were also observed in immunoblotting study. Moreover, these distinctive alterations of protein expression were enhanced by coculture with embryo model. These results indicate that EP can exchange cell polarity in assistance with induction of cell differentiation and evoked EMT. It is important to prepare the receptivity of EEC to catch embryo in the beginning of human implantation. Against the 'prepared' EEC, embryo apposite and then adheres. In this study, we analyzed the adhesion ratio using in in vitro implantation assay. Treatment of EP or SAHA increased the adhesion of EEC to embryo model, compared to untreated Ishikawa cells. After adhesion, embryo outgrows and penetrates through EEC barrier. It is known that apoptosis of EEC is occurred to make space for embryo wide growth and penetration. In addition of cell apoptosis, it is thought to be advantages that EEC slow proliferation and migration away, to keep embryo traffic course. Transfection of glycodelin cDNA caused suppression of cell proliferation through stop at G1/S checkpoint in cell cycle. Treatment of EP and SAHA resulted in broadened embryo outgrowth area, indicating EEC migration away to make space. Subsequently to the destruction of EEC barrier by apoptosis, suppression of c ell proliferation, and migration away, EEC barrier should be reconstructed to protect the undefended top of the penetrating and invading embryo. Probably, quick and loose reconstruction by cell ascending motion is provided to the exposed embryo and then slow and tight reconstruction by cell proliferation is followed. In wound healing assay, motion to cover the vacant space was quickened by stimulation with EP or SAHA. All these regulations were almost completely canceled by glycodelin gene silencing by glycodelin siRNA. In association of Glycodelin-mediated effect, through EMT-mediated upregulation and redistribution of N-cadherin, stimulation with EP or SAHA enhanced migration in both descending and ascending direction to embryo. Collective these results indicate the following mechanism of EEC dynamics; prior to embryo arrival, ovarian steroid hormones prepare the receptivity of EEC to catch embryo by cell differentiation through induction of Glycodelin and driving of EMT. At the next step, apposition between embryo and EEC accelerate and maintain Glycodelin induction and EMT, resulting highly elevation of adhesion activity. EEC barrier dramatic alterations, which is damage followed by reconstruction, are regulate by Glycodelin- and EMT-mediated cell proliferation and cell motility. A key molecule, Glycodelin, orchestrates the continuous designed mechanism of human implantation. Furthermore, SAHA can induce Glycodelin and therefore SAHA can regulate the EEC continuous functions during human implantation, indicating the potential of SAHA as an assistant therapeutic tool for reproductive medicine by targeting Glycodelin.

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